ClinVar Miner

Submissions for variant NM_001130987.2(DYSF):c.953T>A (p.Val318Glu)

dbSNP: rs398123807
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen RCV003330426 SCV005620338 pathogenic Autosomal recessive limb-girdle muscular dystrophy 2025-01-08 reviewed by expert panel curation The NM_003494.4: c.857T>A variant in DYSF, which is also known as NM_001130987.2: c.953T>A p.(Val318Glu), is a missense variant predicted to cause substitution of valine by glutamic acid at amino acid 318 p.(Val318Glu). This variant has been detected in at least 6 unrelated individuals with dysferlinopathy (PMID: 18832576, 25493284, 27602406, 32528171, 33610434, 33927379, 36983702). Of those individuals, two were compound heterozygous for the variant and a confirmed pathogenic or likely pathogenic variant (c.5860G>T p.Glu1954Ter, 1.0 pt, PMID: 33927379; c.2779del p.Ala927LeufsTer21, 1.0 pt, PMID: 18832576 (PM3_Strong). At least one patient with this variant displayed progressive limb girdle muscle weakness and absent dysferlin protein expression in skeletal muscle or blood monocytes, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 18832576). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008 (1/113768 alleles) in the European (non-Finnish) population, which is less than the LGMD VCEP threshold (≤0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting). RNAseq analysis demonstrated that this variant may result in missplicing in a small percentage of transcripts (PMID: 36983702), but the consequences of this degree of missplicing on protein function are unclear (PVS1_RNA not met). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the variant protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). The computational predictor REVEL gives a score of 0.95, which exceeds the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PM2_Supporting, PM3_Strong, PP4_Strong, PS3_Moderate, PP3.
Labcorp Genetics (formerly Invitae), Labcorp RCV000696449 SCV000825012 pathogenic Qualitative or quantitative defects of dysferlin 2023-11-27 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 286 of the DYSF protein (p.Val286Glu). This variant is present in population databases (rs398123807, gnomAD 0.0009%). This missense change has been observed in individual(s) with DYSF-related conditions (PMID: 18832576, 25493284, 32528171, 33610434, 33927379). ClinVar contains an entry for this variant (Variation ID: 94365). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity RCV000080333 SCV003833273 likely pathogenic not provided 2023-01-13 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003330426 SCV004039342 likely pathogenic Autosomal recessive limb-girdle muscular dystrophy 2023-08-03 criteria provided, single submitter clinical testing Variant summary: DYSF c.857T>A (p.Val286Glu) 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. Althought the variant alters the second nucleotide of exon 9 near the 3' splice acceptor junction, computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251494 control chromosomes. c.857T>A has been reported in the literature in compound heterozygous individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive 2B or dysferlinopathy (e.g. Dominov_2014, Harris_2016, Charnay_2021, Kesari_2021, Moore_2021) or in an individual with undiagnosed limb-girdle weakness with unspecified variant zygosity (e.g. Topf_2020). These data indicate that the variant is 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: 24488599, 33927379, 25493284, 27602406, 18832576, 33610434, 32528171). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as likely pathogenic (n=2) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Eurofins Ntd Llc (ga) RCV000080333 SCV000112228 uncertain significance not provided 2012-09-04 flagged submission clinical testing
Natera, Inc. RCV001831823 SCV002079774 uncertain significance Autosomal recessive limb-girdle muscular dystrophy type 2B 2021-01-12 flagged submission clinical testing

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