ClinVar Miner

Submissions for variant NM_000070.3(CAPN3):c.1621C>T (p.Arg541Trp) (rs142004418)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000726807 SCV000703198 pathogenic not provided 2018-08-31 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000762951 SCV000893375 pathogenic Limb-girdle muscular dystrophy, type 2A; Muscular dystrophy, limb-girdle, autosomal dominant 4 2018-10-31 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000595213 SCV001164528 uncertain significance Limb-girdle muscular dystrophy, type 2A 2018-12-03 criteria provided, single submitter research The homozygous p.Arg541Trp variant in CAPN3 was identified by our study in three unrelated individuals with limb-girdle muscular dystrophy (LGMD). The presence of this variant in the homozygous state and in individuals with LGMD increases the likelihood that the p.Arg541Trp variant is pathogenic. This variant has been identified in 0.003656% (9/246196) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs142004418). 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. In summary, the clinical significance of the p.Arg541Trp variant is uncertain. ACMG/AMP Criteria applied: PM2, PM3, PP3 (Richards 2015).
Invitae RCV000595213 SCV001220736 pathogenic Limb-girdle muscular dystrophy, type 2A 2020-06-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 541 of the CAPN3 protein (p.Arg541Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs142004418, ExAC 0.01%). This variant has been observed in individuals with limb-girdle muscular dystrophy (PMID: 16100770, 18854869, 19556129). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 498267). 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 C1). For these reasons, this variant has been classified as Pathogenic. 5
CeGaT Praxis fuer Humangenetik Tuebingen RCV000726807 SCV001247173 pathogenic not provided 2018-03-01 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000726807 SCV001446547 likely pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Counsyl RCV000595213 SCV000797507 likely pathogenic Limb-girdle muscular dystrophy, type 2A 2018-01-30 no assertion criteria provided clinical testing

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