ClinVar Miner

Submissions for variant NM_001130987.2(DYSF):c.6313G>A (p.Ala2105Thr)

gnomAD frequency: 0.00001  dbSNP: rs746663568
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000673203 SCV000798379 uncertain significance Autosomal recessive limb-girdle muscular dystrophy type 2B 2018-03-09 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001035887 SCV001199227 likely pathogenic Qualitative or quantitative defects of dysferlin 2024-10-25 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2066 of the DYSF protein (p.Ala2066Thr). This variant is present in population databases (rs746663568, gnomAD 0.002%). This missense change has been observed in individual(s) with dysferlinopathy and/or limb girdle muscular dystrophy (PMID: 21522182, 27066573, 32400077, 32528171, 34559919; internal data). This variant is also known as c.6313G>A, p.A2105T. ClinVar contains an entry for this variant (Variation ID: 557110). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt DYSF protein function with a negative predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Revvity Omics, Revvity RCV003144473 SCV003831296 uncertain significance not provided 2019-03-14 criteria provided, single submitter clinical testing
Baylor Genetics RCV003465524 SCV004196533 pathogenic Miyoshi muscular dystrophy 1 2024-02-20 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV003144473 SCV005433049 likely pathogenic not provided 2024-09-01 criteria provided, single submitter clinical testing DYSF: PM3:Strong, PM2, PS3:Supporting, BP4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV005240445 SCV005885171 pathogenic Autosomal recessive limb-girdle muscular dystrophy 2024-12-17 criteria provided, single submitter clinical testing Variant summary: DYSF c.6196G>A (p.Ala2066Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250566 control chromosomes (gnomAD). c.6196G>A has been reported in the literature in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive or Miyoshi muscular dystrophy (e.g. Cacciottolo_2011, Arrigoni_2018, Izumi_2020, Topf_2020, Bardakov_2021, Zhong_2021). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 21522182, 30028523, 32528171, 35047756, 34559919, 32400077). ClinVar contains an entry for this variant (Variation ID: 557110). Based on the evidence outlined above, the variant was classified as pathogenic.

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