ClinVar Miner

Submissions for variant NM_001130987.2(DYSF):c.1499G>A (p.Arg500His)

gnomAD frequency: 0.00001  dbSNP: rs775370021
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001322090 SCV001512947 uncertain significance Qualitative or quantitative defects of dysferlin 2022-07-25 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 468 of the DYSF protein (p.Arg468His). This variant is present in population databases (rs775370021, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with DYSF-related conditions. ClinVar contains an entry for this variant (Variation ID: 1022210). 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 not expected to disrupt DYSF protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003399102 SCV004122810 uncertain significance not specified 2023-10-12 criteria provided, single submitter clinical testing Variant summary: DYSF c.1403G>A (p.Arg468His) results in a non-conservative amino acid change located in the C2 domain (IPR000008) 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 1.6e-05 in 251460 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1403G>A has been reported in the literature in individuals affected with dysferlinopathy (example: Nashi_2023). This report does not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy, Autosomal Recessive. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 36580222). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc. RCV001830971 SCV002079802 uncertain significance Autosomal recessive limb-girdle muscular dystrophy type 2B 2020-08-03 no assertion criteria provided clinical testing

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