NM_000070.3(CAPN3):c.2338G>C (p.Asp780His) AND Limb-girdle muscular dystrophy, type 2A

Clinical significance:Pathogenic (Last evaluated: Aug 24, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000176251.8

Allele description [Variation Report for NM_000070.3(CAPN3):c.2338G>C (p.Asp780His)]

NM_000070.3(CAPN3):c.2338G>C (p.Asp780His)

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.2338G>C (p.Asp780His)
HGVS:
  • NC_000015.10:g.42410958G>C
  • NG_008660.1:g.67856G>C
  • NM_000070.3:c.2338G>CMANE SELECT
  • NM_024344.1:c.2320G>C
  • NM_173087.1:c.2062G>C
  • NM_173088.1:c.802G>C
  • NM_173089.1:c.343G>C
  • NM_173090.1:c.343G>C
  • NP_000061.1:p.Asp780His
  • NP_077320.1:p.Asp774His
  • NP_775110.1:p.Asp688His
  • NP_775111.1:p.Asp268His
  • NP_775112.1:p.Asp115His
  • NP_775113.1:p.Asp115His
  • LRG_849t1:c.2338G>C
  • LRG_849:g.67856G>C
  • LRG_849p1:p.Asp780His
  • NC_000015.9:g.42703156G>C
  • NM_000070.2:c.2338G>C
Protein change:
D115H
Links:
dbSNP: rs778768583
NCBI 1000 Genomes Browser:
rs778768583
Molecular consequence:
  • NM_000070.3:c.2338G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_024344.1:c.2320G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_173087.1:c.2062G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_173088.1:c.802G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_173089.1:c.343G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_173090.1:c.343G>C - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

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

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000766714Invitaecriteria provided, single submitter
Pathogenic
(Aug 24, 2019)
germlineclinical testing

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

SCV000789634Counsylno assertion criteria providedLikely pathogenic
(Feb 8, 2017)
unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000844967Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Geneticsno assertion criteria providedPathogenic
(Sep 18, 2018)
germlineclinical testing

SCV001164527Broad Institute Rare Disease Group, Broad Institutecriteria provided, single submitter
Pathogenic
(Dec 3, 2018)
germlineresearch

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
not providedgermlineyesnot providednot providednot providednot providednot providedresearch
Indian Hindugermlineyes1not providednot providednot providednot providedclinical testing

Citations

PubMed

Novel mutations in the calpain 3 gene in Germany.

Todorova A, Kress W, Mueller C.

Clin Genet. 2005 Apr;67(4):356-8. No abstract available.

PubMed [citation]
PMID:
15733273

Limb-girdle muscular dystrophy in the Agarwals: Utility of founder mutations in CAPN3 gene.

Khadilkar SV, Chaudhari CR, Dastur RS, Gaitonde PS, Yadav JG.

Ann Indian Acad Neurol. 2016 Jan-Mar;19(1):108-11. doi: 10.4103/0972-2327.175435.

PubMed [citation]
PMID:
27011640
PMCID:
PMC4782525
See all PubMed Citations (7)

Details of each submission

From Invitae, SCV000766714.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change replaces aspartic acid with histidine at codon 780 of the CAPN3 protein (p.Asp780His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is present in population databases (rs778768583, ExAC 0.006%). This variant has been reported as homozygous and/or in combination with another CAPN3 variant in many individuals affected with limb-girdle muscular dystrophy. It has been described as a founder mutation in the Agarwal community originating from northern India (PMID: 15733273, 25079074, 27011640, 23666804). Experimental studies have shown that this missense change results in reduced protein expression and autolytic activity in muscle biopsy samples (PMID: 25079074). 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, SCV000789634.2

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

From Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics, SCV000844967.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1Indian Hindu1not providednot providedclinical testingnot provided

Description

The observed variant c.2338G>C (p.Asp780His) has not been reported in 1000 Genomes and has a minor allele frequency of 0.002% in the ExAC databases. The In silico prediction of the given variant is probably damaging by PolyPhen-2 and damaging by MutationTaster2 and SIFT. The above variant was observed as compound heterozygous along with the variant g.50431G>T (3'splice site). The variant g.50431G>T (3'splice site) has not been reported in 1000 Genomes and ExAC databases. The in silico prediction of the given variant is damaging by MutationTaster2.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not providednot providednot provided

From Broad Institute Rare Disease Group, Broad Institute, SCV001164527.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearch PubMed (4)

Description

The heterozygous p.Asp780His 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). This variant has been identified in 0.0008124% (2/246172) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs778768583). 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. The variant is located in the well-established functional domain EF-hand 4, a domain involved in protein homodimerization (PMID: 24846670). In vitro functional studies with muscle biopsies provide some evidence that the p.Asp780His variant may impact protein function by reducing translation and autolytic activity (PMID: 25079074). However, these types of assays may not accurately represent biological function. The p.Asp780His variant in CAPN3 has been reported in 7 Indian Agarwal individuals with LGMD and is a known founder mutation in the Indian Agarwal community (PMID: 23666804). The presence of this variant in combination with a pathogenic variant by our study as well as a splice site variant in 5 individuals with LGMD increases the likelihood that the p.Asp780His variant is pathogenic (PMID: 23666804). This variant has also been reported pathogenic and likely pathogenic in ClinVar (Variation ID: 195641). In summary, this variant meets criteria to be classified as pathogenic for LGMD in an autosomal recessive manner based on its location in a well-established functional domain and multiple occurrences with other CAPN3 variants. ACMG/AMP Criteria applied: PM2, PP3, PM1, PS3_Supporting, PM3_Strong (Richards 2015).

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

Last Updated: May 10, 2021

Support Center