ClinVar Miner

Submissions for variant NM_001130987.2(DYSF):c.2844G>C (p.Trp948Cys)

dbSNP: rs727503910
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000153178 SCV000202648 uncertain significance not provided 2016-02-05 criteria provided, single submitter clinical testing
Counsyl RCV000668306 SCV000792884 uncertain significance Autosomal recessive limb-girdle muscular dystrophy type 2B 2017-08-03 criteria provided, single submitter clinical testing
Jain Foundation RCV003329115 SCV004032197 likely pathogenic Qualitative or quantitative defects of dysferlin 2023-03-13 criteria provided, single submitter research This variant is absent from gnomAD v2.1.1. This variant has been reported in individuals with a clinical phenotype consistent with dysferlinopathy, associated with disease range dysferlin protein levels, and found in the heterozygous state in conjuction with the pathogeic or likely pathogenic DYSF variants, c.2643+1G>A, c.4024C>T, or c.3832C>T (PMID: 36983702, 18853459). This variant has also been reported to cause reduced dysferlin protein expression and no plasma membrane localization via an in vitro assay (PMID: 35028538). Both the REVEL (0.867) and CADD (25.7) scores support a deleterious effect. The ACMG classification criteria applied are: PM2 moderate, PM3 moderate, PP3, PP4 moderate, and PS3 supporting. Based on the above data, this variant has been classified as Likely Pathogenic.
Baylor Genetics RCV003462058 SCV004194184 pathogenic Miyoshi muscular dystrophy 1 2023-10-09 criteria provided, single submitter clinical testing
Revvity Omics, Revvity Omics RCV000153178 SCV004238168 likely pathogenic not provided 2023-09-18 criteria provided, single submitter clinical testing
Invitae RCV003329115 SCV004292570 pathogenic Qualitative or quantitative defects of dysferlin 2023-11-17 criteria provided, single submitter clinical testing This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 930 of the DYSF protein (p.Trp930Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with DYSF-related conditions (PMID: 18853459, 33610434). ClinVar contains an entry for this variant (Variation ID: 167021). 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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