ClinVar Miner

Submissions for variant NM_000070.3(CAPN3):c.328C>T (p.Arg110Ter)

dbSNP: rs121434545
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000019181 SCV000790467 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2017-03-21 criteria provided, single submitter clinical testing
Mendelics RCV000019181 SCV001139556 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2019-05-28 criteria provided, single submitter clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000019181 SCV001164492 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2018-12-03 criteria provided, single submitter research The heterozygous p.Arg110Ter variant in CAPN3 was identified by our study in the compound heterozygous state, with another pathogenic variant, in one individual with limb-girdle muscular dystrophy (LGMD). The presence of this variant in combination with a pathogenic variant and in an individual with LGMD increases the likelihood that the p.Arg110Ter variant is pathogenic. This variant has been identified in 0.0008955% (1/111670) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121434545). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 110, which is predicted to lead to a truncated or absent protein. Loss of function of the CAPN3 gene is an established disease mechanism in autosomal recessive LGMD. In summary, this variant meets criteria to be classified as pathogenic for LGMD in an autosomal recessive manner based on the predicted impact of the variant and the presence of another pathogenic variant in one individual with LGMD. ACMG/AMP Criteria applied: PM2, PVS1, PM3 (Richards 2015).
Invitae RCV000019181 SCV001579198 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2023-07-21 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 17615). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive CAPN3-related conditions (PMID: 7720071, 16542520, 30028523). This variant is present in population databases (rs121434545, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Arg110*) in the CAPN3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CAPN3 are known to be pathogenic (PMID: 10330340, 15689361).
DASA RCV001813749 SCV002061251 pathogenic Muscular dystrophy, limb-girdle, autosomal dominant 4 2022-01-05 criteria provided, single submitter clinical testing The c.328C>T;p.(Arg110*) variant creates a premature translational stop signal in the CAPN3 gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID:17615; PMID: 16141003; 7720071; 16542520; 25135358; 30028523; 31931849) - PS4. The variant is present at low allele frequencies population databases (rs121434545– gnomAD 0.0006574%; ABraOM 0.000427 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg110*) was detected in trans with a pathogenic variant (PMID: 26677118; 18854869) - PM3_strong. In summary, the currently available evidence indicates that the variant is pathogenic.
3billion RCV000019181 SCV002521634 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2022-05-22 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000017615). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Baylor Genetics RCV001813749 SCV004213802 pathogenic Muscular dystrophy, limb-girdle, autosomal dominant 4 2023-03-04 criteria provided, single submitter clinical testing
OMIM RCV000019181 SCV000039469 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 1995-04-07 no assertion criteria provided literature only
Natera, Inc. RCV000019181 SCV002094441 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2020-06-10 no assertion criteria provided clinical testing

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