ClinVar Miner

Submissions for variant NM_001130987.2(DYSF):c.3028T>C (p.Trp1010Arg)

dbSNP: rs750028300
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000666237 SCV000790495 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2B 2017-03-31 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000763506 SCV000894296 likely pathogenic Miyoshi muscular dystrophy 1; Autosomal recessive limb-girdle muscular dystrophy type 2B; Distal myopathy with anterior tibial onset 2018-10-31 criteria provided, single submitter clinical testing
Baylor Genetics RCV003465448 SCV004196518 pathogenic Miyoshi muscular dystrophy 1 2023-06-03 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004689834 SCV005185832 pathogenic Autosomal recessive limb-girdle muscular dystrophy 2024-05-14 criteria provided, single submitter clinical testing Variant summary: DYSF c.2974T>C (p.Trp992Arg) results in a non-conservative amino acid change located in the Peroxin/Ferlin domain (Peroxin/Ferlin domain) 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 251480 control chromosomes. c.2974T>C has been reported in the literature either as homozygous or in the compound heterozygous state with a pathogenic variant in multiple individuals affected with autosomal recessive Limb-Girdle Muscular Dystrophy (e.g. Cho_2006, Takahashi_2013, Izumi_2015, Fernandez-Eulate_2021). 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. The following publications have been ascertained in the context of this evaluation (PMID: 16891820, 33715265, 27066573, 23243261). ClinVar contains an entry for this variant (Variation ID: 551236). Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV005091928 SCV005834105 pathogenic Qualitative or quantitative defects of dysferlin 2024-01-30 criteria provided, single submitter clinical testing This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 992 of the DYSF protein (p.Trp992Arg). This variant is present in population databases (rs750028300, gnomAD 0.006%). This missense change has been observed in individual(s) with DYSF-related conditions (PMID: 16891820, 32400077). ClinVar contains an entry for this variant (Variation ID: 551236). 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.

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