ClinVar Miner

Submissions for variant NM_000070.3(CAPN3):c.756GAA[1] (p.Lys254del)

dbSNP: rs794727697
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Total submissions: 12
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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 RCV004998384 SCV005620238 pathogenic Autosomal recessive limb-girdle muscular dystrophy 2025-01-09 reviewed by expert panel curation The NM_000070.3: c.759_761del variant in CAPN3, which is also known as c.756_758del, is predicted to cause a change in the length of the protein due to an in-frame deletion of one amino acid in a non-repeat region, p.(Lys254del) (PM4). This variant has been detected in at least 11 unrelated individuals with limb girdle muscular dystrophy (PMID: 26886200, 10330340, 16141003, 18055493, 30564623, 12461690, 35731190), including in a homozygous state in one case (0.5 pts; PMID: 18055493), confirmed in trans with a pathogenic variant in three cases (c.1468C>T p.(Arg490Trp), 1.0 pt, PMID: 12461690; c.1746-20C>G, 2.0 pts, PMID: 35731190), and in unknown phase with a pathogenic variant in one case (c.1468C>T p.(Arg490Trp), 0.5 pts, PMID: 18055493) (PM3_Very Strong). At least one patient with this variant displayed progressive limb girdle muscle weakness or a clinical suspicion of LGMD (PP4). The filtering allele frequency of the variant is 0.0001933 for European (non-Finnish) genome alleles in gnomAD v3.1.2 (the upper threshold of the 95% CI of 7/68016), which is greater than the LGMD VCEP threshold (<0.0001) for PM2_Supporting (criterion not met). 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; 01/09/2025): PM4, PM3_Very Strong, PP4.
Eurofins Ntd Llc (ga) RCV000412949 SCV000230841 pathogenic not provided 2018-02-28 criteria provided, single submitter clinical testing
GeneDx RCV000412949 SCV000490451 pathogenic not provided 2023-05-25 criteria provided, single submitter clinical testing In-frame deletion of 1 amino acid in a non-repeat region predicted to critically alter the protein; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22622166, 20694146, 34720847, 26810512, 16141003, 10330340, 28300015, 12461690, 27447704, 16344536, 18334579, 18563459, 30564623, 30919934, 31980526, 33741228, 32528171, 18055493)
Labcorp Genetics (formerly Invitae), Labcorp RCV000178708 SCV000645512 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2025-01-20 criteria provided, single submitter clinical testing This variant, c.759_761del, results in the deletion of 1 amino acid(s) of the CAPN3 protein (p.Lys254del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs760168012, gnomAD 0.01%). This variant has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 10330340, 16141003, 18055493, 18334579, 18563459, 20694146, 22622166). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 197624). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen RCV000412949 SCV001247164 pathogenic not provided 2023-10-01 criteria provided, single submitter clinical testing CAPN3: PM3:Very Strong, PM2, PM4:Supporting
Athena Diagnostics RCV000412949 SCV001879828 pathogenic not provided 2020-10-27 criteria provided, single submitter clinical testing The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.
Revvity Omics, Revvity RCV000412949 SCV002018040 pathogenic not provided 2023-10-26 criteria provided, single submitter clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV002252023 SCV002523010 likely pathogenic See cases 2022-02-03 criteria provided, single submitter clinical testing ACMG classification criteria: PS3, PS4, PM4
Baylor Genetics RCV003474934 SCV004211560 likely pathogenic Muscular dystrophy, limb-girdle, autosomal dominant 4 2024-03-23 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV005008105 SCV005635667 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A; Muscular dystrophy, limb-girdle, autosomal dominant 4 2024-05-29 criteria provided, single submitter clinical testing
Counsyl RCV000178708 SCV001132349 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2017-07-28 no assertion criteria provided clinical testing
Natera, Inc. RCV000178708 SCV002094457 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2021-05-06 no assertion criteria provided clinical testing

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