Submissions for variant NM_001130987.2(DYSF):c.1116C>G (p.Ser372Arg)

dbSNP: rs766891289

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001067684	SCV001232755	pathogenic	Qualitative or quantitative defects of dysferlin	2023-07-31	criteria provided, single submitter	clinical testing	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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DYSF protein function. This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 340 of the DYSF protein (p.Ser340Arg). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with DYSF-related conditions (PMID: 17698709, 21522182, 26404900, 33610434). ClinVar contains an entry for this variant (Variation ID: 288183). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000336319	SCV001999483	likely pathogenic	not provided	2023-02-28	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25312915, 32153140, 24438169, 19730931, 17698709, 35047756, 26404900, 33610434, 21522182, 19556129)
Neuberg Centre For Genomic Medicine, NCGM	RCV001823131	SCV002073234	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2B		criteria provided, single submitter	clinical testing	The missense variant p.S340R in DYSF (NM_003494.4) has been reported previously multiple affected individuals with dysferlinopathy (Cacciottolo M et al; Magri F et al). The reported indviduals harbor a different nucleotide change c.1020C>A but the same amino acid variant. The variant has been submitted to clinvar with conflicting interpretations: VUS/Likely Pathogenic. This variant is also referred to as Ser372Arg on a different transcript. The p.S340R variant is observed in 1/1,13,756 (0.0009%) alleles from individuals of European (Non-Finnish) background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.S340R missense variant is predicted to be damaging by both SIFT and PolyPhen2. The serine residue at codon 340 of DYSF is conserved in all mammalian species. The nucleotide c.1020 in DYSF is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004800374	SCV005423187	pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2024-10-30	criteria provided, single submitter	clinical testing	Variant summary: DYSF c.1020C>G (p.Ser340Arg) results in a non-conservative amino acid change located in the Ferlin domain (IPR012968) of 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 251482 control chromosomes. c.1020C>G has been reported in the literature in the homozygous state in at least 1 individual affected with dysferlinopathy (example, Harris_2016). Further, a different c. with identical protein effect (c.1020C>A p.Ser340Arg) is pathogenic (PMID: 17698709, 21522182, 26404900). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results total loss of detectable DYSF protein in muscle tissue (example, Harris_2016). The following publication has been ascertained in the context of this evaluation (PMID: 27602406). ClinVar contains an entry for this variant (Variation ID: 288183). Based on the evidence outlined above, the variant was classified as pathogenic.
Eurofins Ntd Llc (ga)	RCV000336319	SCV000342218	uncertain significance	not provided	2016-05-23	flagged submission	clinical testing