NM_000070.3(CAPN3):c.1477C>T (p.Arg493Trp) AND Limb-girdle muscular dystrophy, type 2A

Clinical significance:Likely pathogenic (Last evaluated: Feb 20, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000201107.6

Allele description [Variation Report for NM_000070.3(CAPN3):c.1477C>T (p.Arg493Trp)]

NM_000070.3(CAPN3):c.1477C>T (p.Arg493Trp)

Gene:
CAPN3:calpain 3 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
15q15.1
Genomic location:
Preferred name:
NM_000070.3(CAPN3):c.1477C>T (p.Arg493Trp)
HGVS:
  • NC_000015.10:g.42401763C>T
  • NG_008660.1:g.58661C>T
  • NM_000070.3:c.1477C>TMANE SELECT
  • NM_024344.1:c.1477C>T
  • NM_173087.1:c.1333C>T
  • NP_000061.1:p.Arg493Trp
  • NP_077320.1:p.Arg493Trp
  • NP_775110.1:p.Arg445Trp
  • LRG_849t1:c.1477C>T
  • LRG_849:g.58661C>T
  • LRG_849p1:p.Arg493Trp
  • NC_000015.9:g.42693961C>T
  • NM_000070.2:c.1477C>T
  • P20807:p.Arg493Trp
Protein change:
R445W
Links:
UniProtKB: P20807#VAR_009585; dbSNP: rs557164942
NCBI 1000 Genomes Browser:
rs557164942
Molecular consequence:
  • NM_000070.3:c.1477C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_024344.1:c.1477C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_173087.1:c.1333C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Limb-girdle muscular dystrophy, type 2A (LGMDR1)
Synonyms:
Limb-girdle muscular dystrophy type 2; Muscular dystrophy, pelvofemoral; Leyden-Moebius muscular dystrophy; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0009675; MedGen: C1869123; Orphanet: 267; OMIM: 253600

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000791903Counsylno assertion criteria providedLikely pathogenic
(May 31, 2017)
unknownclinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV001387850Invitaecriteria provided, single submitter
Likely pathogenic
(Feb 20, 2020)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Analysis of the UK diagnostic strategy for limb girdle muscular dystrophy 2A.

Groen EJ, Charlton R, Barresi R, Anderson LV, Eagle M, Hudson J, Koref MS, Straub V, Bushby KM.

Brain. 2007 Dec;130(Pt 12):3237-49.

PubMed [citation]
PMID:
18055493

Discovery of pathogenic variants in a large Korean cohort of inherited muscular disorders.

Park HJ, Jang H, Kim JH, Lee JH, Shin HY, Kim SM, Park KD, Yim SV, Lee JH, Choi YC.

Clin Genet. 2017 Mar;91(3):403-410. doi: 10.1111/cge.12826. Epub 2016 Jul 29.

PubMed [citation]
PMID:
27363342
See all PubMed Citations (8)

Details of each submission

From Counsyl, SCV000791903.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001387850.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This sequence change replaces arginine with tryptophan at codon 493 of the CAPN3 protein (p.Arg493Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs557164942, ExAC 0.003%). This variant has been observed in several individuals affected with autosomal recessive limb-girdle muscular dystrophy (PMID: 10330340, 18334579, 17236769, 18073330, 25079074). ClinVar contains an entry for this variant (Variation ID: 193792). 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 C0). 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 10, 2021

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