# NM_004168.4(SDHA):c.1663+5G>C

https://sugi.bio/variant/sdha-c-1663-plus-5g-c

## Summary

**SDHA c.1663+5G>C** is classified **Conflicting classifications of pathogenicity** in SDHA (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-06). Absent from gnomAD v4.1; Associated with dilated cardiomyopathy 1GG.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs1736797211 · 5 submitters · 4 linked conditions · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the SDHA gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 5 submitters, and is linked to dilated cardiomyopathy 1GG.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive, Mitochondrial inheritance |
| Age of onset (of this condition) | All ages |
| Prevalence | 1-9 / 100 000 (Europe) |
| Diagnostic panels | SDHA is a diagnostic-grade gene on 18 Genomics England panels |

**Commonly reported features of Familial isolated dilated cardiomyopathy** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Dilated cardiomyopathy — Very frequent (99-80%)
- Left ventricular systolic dysfunction — Very frequent (99-80%)
- Edema — Frequent (79-30%)
- Congestive heart failure — Frequent (79-30%)
- Exertional dyspnea — Frequent (79-30%)
- Arrhythmia — Frequent (79-30%)
- Fatigue — Frequent (79-30%)
- Orthopnea — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015684/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SDHA](https://sugi.bio/atlas/gene/SDHA/) |
| Coding change (HGVS c.) | c.1663+5G>C |
| MANE Select transcript | [NM_004168](https://www.ncbi.nlm.nih.gov/nuccore/NM_004168) |
| dbSNP | [rs1736797211](https://www.ncbi.nlm.nih.gov/snp/rs1736797211/) |
| Variant type | single nucleotide variant |
| Location | chr5:251108-251108 (GRCh38) |
| ClinVar | [VCV844105](https://www.ncbi.nlm.nih.gov/clinvar/variation/844105/) |

**All HGVS expressions:** `LRG_315:g.37868G>C`, `LRG_315t1:c.1663+5G>C`, `NC_000005.10:g.251108G>C`, `NC_000005.9:g.251223G>C`, `NG_012339.1:g.37868G>C`, `NM_001294332.2:c.1519+5G>C`, `NM_001330758.2:c.1552-3285G>C`, `NM_004168.2:c.1663+5G>C`, `NM_004168.4:c.1663+5G>C`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.93) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 11.286, GERP 1.4, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 18.04**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Splice region: **donor splice region (+5, within the first 6 intronic nt)** — inside the zone ClinGen GN167 excludes from BP7, so this variant must not be called benign merely for being synonymous or intronic.
- Non-coding constraint (Gnocchi): **Z 2.75**, o/e 0.78 (1 kb window 251,000–252,000). A higher Z means the window carries less variation than expected. Describes the 1 kb window, not this allele. No ClinGen expert panel references Gnocchi and no ACMG-calibrated threshold exists for it. *Descriptive; no cut-point applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.93**, acceptor gain **0.00**, donor gain **0.04**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.93**, acceptor gain **0.00**, donor gain **0.04**.
- Pangolin: Δ**0.80** (loss), gain 0.01 / loss 0.80. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**SDHA** population constraint: LOEUF 0.786, pLI 3.3694e-08, missense-Z 2.306. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **hereditary pheochromocytoma-paraganglioma** — Definitive (AD)
- **Leigh syndrome** — Moderate (AR)
- **mitochondrial disease** — Definitive (AR)
- **mitochondrial disease** — Limited (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 94.06, 92% of residues very-high.

**5 experimental structure(s)** (PDB): [6VAX](https://www.rcsb.org/structure/6VAX), [8DYD](https://www.rcsb.org/structure/8DYD), [8DYE](https://www.rcsb.org/structure/8DYE), [8GS8](https://www.rcsb.org/structure/8GS8), [9KC4](https://www.rcsb.org/structure/9KC4).

## What this gene does {#gene-function}

*Describes the biological roles of SDHA (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** SDHA's established molecular role includes succinate dehydrogenase (quinone) activity.


### Pathways affected {#pathways}

SDHA participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Citric acid cycle (TCA cycle)](https://reactome.org/content/detail/R-HSA-71403) | curated |
| [Maturation of TCA enzymes and regulation of TCA cycle](https://reactome.org/content/detail/R-HSA-9854311) | curated |
| [Respiratory electron transport](https://reactome.org/content/detail/R-HSA-611105) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** succinate dehydrogenase (quinone) activity.

**Biological process:** succinate metabolic process, nervous system development, respiratory electron transport chain.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-06.

**Submitter consensus:** conflicting (3 Uncertain significance, 2 Likely pathogenic).

**Submission history:** 5 submissions (2024–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Baylor Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-01-08 |
| Quest Diagnostics Nichols Institute San Juan Capistrano | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-05-02 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-11-06 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-08-10 |
| Myriad Genetics, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2026-01-06 |

## Associated conditions {#conditions}

[dilated cardiomyopathy 1GG](https://sugi.bio/atlas/disease/dilated-cardiomyopathy-1gg/), [pheochromocytoma/paraganglioma syndrome 5](https://sugi.bio/atlas/disease/pheochromocytoma-paraganglioma-syndrome-5/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/), [mitochondrial complex II deficiency, nuclear type 1](https://sugi.bio/atlas/disease/mitochondrial-complex-ii-deficiency-nuclear-type-1/).

**Reported phenotype names (ClinVar):** Dilated cardiomyopathy 1GG, Mitochondrial complex II deficiency, nuclear type 1, Pheochromocytoma/paraganglioma syndrome 5, Hereditary cancer-predisposing syndrome, not provided, none provided, Paragangliomas 5, SDHA-Related Hereditary Paraganglioma-Pheochromocytoma Syndrome, SUCCINATE CoQ REDUCTASE DEFICIENCY, Tumor predisposition.

## Similar variants {#similar}

Related SDHA variant pages (same residue, condition, or type): [SDHA c.1064+1G>A](/variant/sdha-c-1064-plus-1g-a), [SDHA c.1064+1G>T](/variant/sdha-c-1064-plus-1g-t), [SDHA c.1064+2T>A](/variant/sdha-c-1064-plus-2t-a), [SDHA c.1065-2A>G](/variant/sdha-c-1065-minus-2a-g), [SDHA c.1260+1G>T](/variant/sdha-c-1260-plus-1g-t), [SDHA c.1260+2T>A](/variant/sdha-c-1260-plus-2t-a), [SDHA c.1261-1G>A](/variant/sdha-c-1261-minus-1g-a), [SDHA c.1261-2A>G](/variant/sdha-c-1261-minus-2a-g).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 844105). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*