NM_000070.3(CAPN3):c.1621C>T (p.Arg541Trp) AND Autosomal recessive limb-girdle muscular dystrophy type 2A

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Apr 11, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000595213.15

Allele description [Variation Report for NM_000070.3(CAPN3):c.1621C>T (p.Arg541Trp)]

NM_000070.3(CAPN3):c.1621C>T (p.Arg541Trp)

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.1621C>T (p.Arg541Trp)

HGVS:

NC_000015.10:g.42402878C>T
NG_008660.1:g.59776C>T
NM_000070.3:c.1621C>TMANE SELECT
NM_024344.2:c.1621C>T
NM_173087.2:c.1477C>T
NM_173088.2:c.85C>T
NP_000061.1:p.Arg541Trp
NP_077320.1:p.Arg541Trp
NP_775110.1:p.Arg493Trp
NP_775111.1:p.Arg29Trp
LRG_849t1:c.1621C>T
LRG_849:g.59776C>T
LRG_849p1:p.Arg541Trp
NC_000015.9:g.42695076C>T
NM_000070.2:c.1621C>T
p.Arg541Trp

Protein change:

R29W

Links:

dbSNP: rs142004418

NCBI 1000 Genomes Browser:

rs142004418

Molecular consequence:

NM_000070.3:c.1621C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_024344.2:c.1621C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_173087.2:c.1477C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_173088.2:c.85C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000797507	Counsyl	no assertion criteria provided	Likely pathogenic (Jan 30, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001164528	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 11, 2024)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV001220736	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 4, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16100770, 18854869, 19556129, 28492532
SCV002085529	Natera, Inc.	no assertion criteria provided	Pathogenic (Dec 14, 2020)	germline	clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Extensive scanning of the calpain-3 gene broadens the spectrum of LGMD2A phenotypes.

Piluso G, Politano L, Aurino S, Fanin M, Ricci E, Ventriglia VM, Belsito A, Totaro A, Saccone V, Topaloglu H, Nascimbeni AC, Fulizio L, Broccolini A, Canki-Klain N, Comi LI, Nigro G, Angelini C, Nigro V.

J Med Genet. 2005 Sep;42(9):686-93.

PubMed [citation]

PMID:: 16141003
PMCID:: PMC1736133

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

See all PubMed Citations (6)

Details of each submission

From Counsyl, SCV000797507.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001164528.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

Description

The p.Arg541Trp variant in CAPN3 was identified by our study in 1 individual, in the homozygous state, with autosomal recessive limb-girdle muscular dystrophy. The p.Tyr170Cys variant has been reported in at least 9 individuals with limb-girdle muscular dystrophy (PMID: 14981715, 25214167, 30919934, 32576226, 18854869, 19556129), and has been identified in 0.004% (2/44898) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs142004418). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 498267) and has been interpreted as likely pathogenic or pathogenic by multiple submitters. Of the ten affected individuals, four were compound heterozygotes that carried reported pathogenic variant in trans or with unknown phase, which increases the likelihood that the p.Ser226Leu variant is pathogenic (Variation ID: 280037, 282411, 166786, 92414; (PMID: 25214167, 32576226, 18854869, 19556129). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional pathogenic variant, resulting in a different amino acid change at the same position, p.Arg541Gln, has been reported in association with disease in the ClinVar, slightly supporting that a change at this position may not be tolerated (Variation ID: 92407). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive limb-girdle muscular dystrophy. ACMG/AMP Criteria applied: PM3_strong, PP3_moderate, PM2_supporting, PM5_supporting (Richards 2015).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001220736.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 541 of the CAPN3 protein (p.Arg541Trp). This variant is present in population databases (rs142004418, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 16100770, 18854869, 19556129). 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: 498267). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CAPN3 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV002085529.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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