Submissions for variant NM_001130987.2(DYSF):c.5194C>T (p.Arg1732Trp)

dbSNP: rs863225021

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics Inc	RCV000723532	SCV000255772	likely pathogenic	not provided	2018-12-03	criteria provided, single submitter	clinical testing	The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Occurs in three or more cases with a recessive pathogenic variant in the same gene.
Eurofins Ntd Llc (ga)	RCV000723532	SCV000331251	pathogenic	not provided	2015-09-15	criteria provided, single submitter	clinical testing
Invitae	RCV000553055	SCV000649719	pathogenic	Qualitative or quantitative defects of dysferlin	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1693 of the DYSF protein (p.Arg1693Trp). This variant is present in population databases (no rsID available, gnomAD 0.004%). This missense change has been observed in individuals with dysferlinopathy (PMID: 16100712, 23530687, 26088049, 27066573, 27647186). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 217227). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DYSF protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000201092	SCV001164481	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2B	2018-12-03	criteria provided, single submitter	research	The homozygous p.Arg1732Trp variant (sometimes called p.Arg1693Trp in the literature) was identified by our study in two siblings with limb-girdle muscular dystrophy (LGMD). This variant has been identified in 0.0007262% (2/275404) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs863225021). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Arg1732Trp variant in DYSF has been reported in 4 additional individuals with LGMD in the literature and segregated with disease in 4 affected relatives from 2 families reported here and in the literature (PMID: 16100712, 27066573, 27647186). The presence of this variant in combination with a variant not reported in ClinVar and in an individual with LGMD slightly increases the likelihood that the p.Arg1732Trp variant is pathogenic. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PP1_Moderate, PP3, PM3_Supporting (Richards 2015).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509296	SCV002819476	pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2022-12-12	criteria provided, single submitter	clinical testing	Variant summary: DYSF c.5077C>T (p.Arg1693Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249662 control chromosomes. c.5077C>T has been reported in the literature as biallelic homozygous or compound heterozygous genotypes in multiple individuals affected with features of Limb-Girdle Muscular Dystrophy, Autosomal Recessive (example, Cagliani_2005, Izumi_2015, Harris_2016, ten Dam_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000723532	SCV003825641	pathogenic	not provided	2022-10-27	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003468915	SCV004196511	pathogenic	Miyoshi muscular dystrophy 1	2023-06-19	criteria provided, single submitter	clinical testing
Counsyl	RCV000201092	SCV000791027	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2B	2017-04-19	no assertion criteria provided	clinical testing