Noonan syndrome-like disorder with loose anagen hair 1

Summary

Noonan syndrome-like disorder with loose anagen hair 1 (MONDO:0054637) is a disease caused by SHOC2 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: SHOC2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 89

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Noonan syndrome-like disorder with loose anagen hair 1
Mondo ID	MONDO:0054637
OMIM	607721
DOID	DOID:0080692
NCIT	C176939
UMLS	C4478716
MedGen	1379805
GARD	0025955
Is cancer (heuristic)	no

Also known as: Noonan syndrome-like disorder with loose anagen hair 1 · Noonan syndrome-like with loose anagen hair 1 · NSLH · NSLH1

Data availability: 89 ClinVar variants · 1 ClinGen variant curation · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › disorder of pilosebaceous unit › hair anomaly › alopecia › loose anagen syndrome › Noonan syndrome-like disorder with loose anagen hair › Noonan syndrome-like disorder with loose anagen hair 1

Related subtypes (1): Noonan syndrome-like disorder with loose anagen hair 2

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

89 retrieved; paginated sample, class counts are floors:

43 uncertain significance, 18 benign, 15 conflicting classifications of pathogenicity, 7 benign/likely benign, 3 pathogenic, 2 likely benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
181528	NM_007373.4(SHOC2):c.519G>A (p.Met173Ile)	SHOC2	Pathogenic	reviewed by expert panel
6821	NM_007373.4(SHOC2):c.4A>G (p.Ser2Gly)	SHOC2	Pathogenic	reviewed by expert panel
973849	NM_007373.4(SHOC2):c.807_808delinsTT (p.Gln269_His270delinsHisTyr)	SHOC2	Pathogenic	no assertion criteria provided
1339314	NM_007373.4(SHOC2):c.157G>A (p.Gly53Arg)	SHOC2	Likely pathogenic	criteria provided, single submitter
139105	NM_007373.4(SHOC2):c.-244G>T	LOC130004755	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
179760	NM_007373.4(SHOC2):c.170C>T (p.Ser57Phe)	SHOC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
181527	NM_007373.4(SHOC2):c.355A>G (p.Ile119Val)	SHOC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
218698	NM_007373.4(SHOC2):c.806A>G (p.Gln269Arg)	SHOC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
240838	NM_007373.4(SHOC2):c.610A>G (p.Ile204Val)	SHOC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
298862	NM_007373.4(SHOC2):c.774A>G (p.Gly258=)	SHOC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
298866	NM_007373.4(SHOC2):c.*404A>G	SHOC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
298871	NM_007373.4(SHOC2):c.*656C>G	SHOC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
373090	NM_007373.4(SHOC2):c.517A>G (p.Met173Val)	SHOC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
40632	NM_007373.4(SHOC2):c.-159T>C	SHOC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
40633	NM_007373.4(SHOC2):c.-114C>G	SHOC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
40637	NM_007373.4(SHOC2):c.74A>G (p.Glu25Gly)	SHOC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
546129	NM_007373.4(SHOC2):c.519G>T (p.Met173Ile)	SHOC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
976139	NM_007373.4(SHOC2):c.1439A>C (p.Asn480Thr)	SHOC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
981608	NM_007373.4(SHOC2):c.187G>A (p.Gly63Arg)	SHOC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
298859	NM_007373.4(SHOC2):c.-254C>T	LOC130004755	Uncertain significance	criteria provided, single submitter
877713	NM_007373.4(SHOC2):c.-235+15A>G	LOC130004755	Uncertain significance	criteria provided, single submitter
880483	NM_007373.3(SHOC2):c.-346T>G	LOC130004755	Uncertain significance	criteria provided, single submitter
880484	NM_007373.4(SHOC2):c.-264A>T	LOC130004755	Uncertain significance	criteria provided, single submitter
880485	NM_007373.4(SHOC2):c.-259G>A	LOC130004755	Uncertain significance	criteria provided, single submitter
1014118	NM_007373.4(SHOC2):c.233C>T (p.Ala78Val)	SHOC2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1030214	NM_007373.4(SHOC2):c.506_507delinsC (p.Lys169fs)	SHOC2	Uncertain significance	criteria provided, single submitter
1030215	NM_007373.4(SHOC2):c.836C>T (p.Thr279Ile)	SHOC2	Uncertain significance	criteria provided, single submitter
1352714	NM_007373.4(SHOC2):c.743A>G (p.Asn248Ser)	SHOC2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1354851	NM_007373.4(SHOC2):c.1660A>G (p.Ser554Gly)	SHOC2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1484743	NM_007373.4(SHOC2):c.1555C>G (p.Leu519Val)	SHOC2	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
SHOC2	Definitive	Autosomal dominant	Noonan syndrome-like disorder with loose anagen hair	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SHOC2	Orphanet:2701	Noonan syndrome-like disorder with loose anagen hair

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SHOC2	HGNC:15454	ENSG00000108061	Q9UQ13	Leucine-rich repeat protein SHOC-2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SHOC2	Leucine-rich repeat protein SHOC-2	Core component of the SHOC2-MRAS-PP1c (SMP) holophosphatase complex that regulates activation of the MAPK pathway.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SHOC2	Other/Unknown	no		Leu-rich_rpt, Leu-rich_rpt_typical-subtyp, LRR_dom_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bone marrow	1
calcaneal tendon	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SHOC2	299	ubiquitous	marker	calcaneal tendon, sural nerve, bone marrow

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SHOC2	2,149

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SHOC2	Q9UQ13	13

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Signaling by MRAS-complex mutants	1	2855.0×	0.003	SHOC2
SHOC2 M1731 mutant abolishes MRAS complex function	1	1427.5×	0.003	SHOC2
Gain-of-function MRAS complexes activate RAF signaling	1	1427.5×	0.003	SHOC2
RAF activation	1	335.9×	0.008	SHOC2
Oncogenic MAPK signaling	1	248.3×	0.009	SHOC2
MAPK1/MAPK3 signaling	1	131.3×	0.014	SHOC2
MAPK family signaling cascades	1	102.9×	0.015	SHOC2
RAF/MAP kinase cascade	1	61.1×	0.022	SHOC2
Diseases of signal transduction by growth factor receptors and second messengers	1	56.8×	0.022	SHOC2
Disease	1	13.1×	0.084	SHOC2
Signal Transduction	1	10.2×	0.098	SHOC2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cellular response to growth hormone stimulus	1	16852.0×	7e-04	SHOC2
cyclic-GMP-AMP transmembrane import across plasma membrane	1	2106.5×	0.002	SHOC2
negative regulation of neural precursor cell proliferation	1	1532.0×	0.002	SHOC2
nerve growth factor signaling pathway	1	1296.3×	0.002	SHOC2
positive regulation of Ras protein signal transduction	1	887.0×	0.002	SHOC2
regulation of MAPK cascade	1	455.5×	0.004	SHOC2
fibroblast growth factor receptor signaling pathway	1	285.6×	0.005	SHOC2
negative regulation of neuron differentiation	1	271.8×	0.005	SHOC2
positive regulation of neuron differentiation	1	198.3×	0.006	SHOC2
positive regulation of neuron projection development	1	137.0×	0.008	SHOC2
intracellular signal transduction	1	38.1×	0.026	SHOC2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SHOC2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SHOC2

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
SHOC2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.