ClinVar Miner

Submissions for variant NM_001130987.2(DYSF):c.5194C>T (p.Arg1732Trp) (rs863225021)

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Total submissions: 5
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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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000723532 SCV000331251 pathogenic not provided 2015-09-15 criteria provided, single submitter clinical testing
Invitae RCV000553055 SCV000649719 pathogenic Qualitative or quantitative defects of dysferlin 2019-11-12 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 1693 of the DYSF protein (p.Arg1693Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed as homozygous or compound heterozygous in several individuals affected with dysferlinopathy and to segregate with dysferlinopathy in a family (PMID: 16100712, 27066573, 23530687, 27647186, 26088049). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Broad Institute Rare Disease Group, Broad Institute 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).
Counsyl RCV000201092 SCV000791027 likely pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2B 2017-04-19 no assertion criteria provided clinical testing

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