DYSF p.Leu1359Pro

The NM_003494.4: c.4022T>C variant in DYSF, which is also known as NM_001130987.2: c.4076T>C p.(Leu1359Pro), is a missense variant predicted to cause substitution of leucine by proline at amino acid 1341 (p.Leu1341Pro). This variant has been detected in a homozygous state in at least seven individuals with clinical signs of limb girdle muscular dystrophy (1.0 pt, PMID: 16705711, 19528035, 22057634, 26436962, 27647186, 28403181, 34559919, 34624274) (PM3). It has also been observed in trans with a nonsense variant, c.4228C>T p.(Gln1410Ter), in one affected individual (PMID: 34624274). At least one patient with this variant displayed progressive limb girdle muscle weakness and absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 16705711, 21522182). The variant was also reported to co-segregate with the disease in six affected family members from three families (PMID: 16705711, 21522182, 34624274) (PP1, capped with PP4_Strong). The filtering allele frequency of the variants is 0.0003434 for South Asian exome alleles in gnomAD v2.1.1 (the upper threshold of the 95% CI of 5/30616), which is greater than the LGMD VCEP threshold (<0.0001) for PM2_Supporting (criterion not met). Knock-in mice homozygous for the murine equivalent of the human p.Leu1341Pro variant recapitulated key features of dysferlinopathy observed in human patients and tissue, including signs of progressive muscular dystrophy with onset in early adulthood, severely reduced expression of dysferlin at the plasma membrane in skeletal muscle, amyloid deposition, and delayed membrane repair (PMID: 30292141) (PS3). In addition, immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Leu1341Pro protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538). The computational predictor REVEL gives a score of 0.89, which exceeds the VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb-girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PM3, PP4_Strong, PP1, PS3, PP3.