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

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jan 12, 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:: RCV000201107.12

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_024344.2:c.1477C>T
NM_173087.2: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_024344.2:c.1477C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_173087.2:c.1333C>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
SCV000791903	Counsyl	no assertion criteria provided	Likely pathogenic (May 31, 2017)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 10330340, 25079074, 17236769, 18055493, 27363342
SCV001387850	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 12, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 10330340, 17236769, 18073330, 18334579, 25079074, 28492532
SCV004047724	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000791903

Counsyl

no assertion criteria provided

Likely pathogenic
(May 31, 2017)

unknown

clinical testing

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

SCV001387850

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 12, 2024)

germline

clinical testing

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

SCV004047724

Neuberg Centre For Genomic Medicine, NCGM

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic

germline

clinical testing

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

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	clinical testing
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

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 (9)

Details of each submission

From Counsyl, SCV000791903.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001387850.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 493 of the CAPN3 protein (p.Arg493Trp). This variant is present in population databases (rs557164942, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 10330340, 17236769, 18073330, 18334579, 25079074). ClinVar contains an entry for this variant (Variation ID: 193792). 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 Neuberg Centre For Genomic Medicine, NCGM, SCV004047724.1

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

Description

The CAPN3 c.1477C>T variant has been reported in individuals affected with Muscular dystrophy, limb-girdle, autosomal recessive 1 (Nilsson et. al., 2014; Benayoun et. al., 2008). The p.Arg493Trp variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.002832% in gnomAD database. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. 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; PolyPhen2: 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. The amino acid Arg at position 493 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Likely Pathogenic.

#	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

Last Updated: Sep 29, 2024

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