NM_000070.3(CAPN3):c.2305C>T (p.Arg769Trp) AND Limb-girdle muscular dystrophy, type 2A

Clinical significance:Pathogenic (Last evaluated: Jul 13, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000295812.7

Allele description [Variation Report for NM_000070.3(CAPN3):c.2305C>T (p.Arg769Trp)]

NM_000070.3(CAPN3):c.2305C>T (p.Arg769Trp)

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.2305C>T (p.Arg769Trp)
HGVS:
  • NC_000015.10:g.42410925C>T
  • NG_008660.1:g.67823C>T
  • NM_000070.3:c.2305C>TMANE SELECT
  • NM_024344.1:c.2287C>T
  • NM_173087.1:c.2029C>T
  • NM_173088.1:c.769C>T
  • NM_173089.1:c.310C>T
  • NM_173090.1:c.310C>T
  • NP_000061.1:p.Arg769Trp
  • NP_077320.1:p.Arg763Trp
  • NP_775110.1:p.Arg677Trp
  • NP_775111.1:p.Arg257Trp
  • NP_775112.1:p.Arg104Trp
  • NP_775113.1:p.Arg104Trp
  • LRG_849t1:c.2305C>T
  • LRG_849:g.67823C>T
  • LRG_849p1:p.Arg769Trp
  • NC_000015.9:g.42703123C>T
  • NM_000070.2:c.2305C>T
Protein change:
R104W
Links:
dbSNP: rs868791726
NCBI 1000 Genomes Browser:
rs868791726
Molecular consequence:
  • NM_000070.3:c.2305C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_024344.1:c.2287C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_173087.1:c.2029C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_173088.1:c.769C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_173089.1:c.310C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_173090.1:c.310C>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
SCV000645494Invitaecriteria provided, single submitter
Pathogenic
(Jul 13, 2020)
germlineclinical testing

PubMed (10)
[See all records that cite these PMIDs]

SCV000791434Counsylno assertion criteria providedLikely pathogenic
(May 16, 2017)
unknownclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Summary from all submissions

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

Citations

PubMed

cannot get document summary

Mutations in the proteolytic enzyme calpain 3 cause limb-girdle muscular dystrophy type 2A.

Richard I, Broux O, Allamand V, Fougerousse F, Chiannilkulchai N, Bourg N, Brenguier L, Devaud C, Pasturaud P, Roudaut C, et al.

Cell. 1995 Apr 7;81(1):27-40.

PubMed [citation]
PMID:
7720071
See all PubMed Citations (11)

Details of each submission

From Invitae, SCV000645494.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (10)

Description

This sequence change replaces arginine with tryptophan at codon 769 of the CAPN3 protein (p.Arg769Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with autosomal recessive limb-girdle muscular dystrophy (PMID: 205172126, 27066551, 26060040, 28403181). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Arg769 amino acid residue in CAPN3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7720071, 12461690, 7795603, 7762565, 14645990). This suggests that this residue is clinically-significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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

From Counsyl, SCV000791434.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 27, 2021

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