NM_000070.3(CAPN3):c.1063C>T (p.Arg355Trp) AND Autosomal recessive limb-girdle muscular dystrophy type 2A

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Sep 24, 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:: RCV000389096.13

Allele description [Variation Report for NM_000070.3(CAPN3):c.1063C>T (p.Arg355Trp)]

NM_000070.3(CAPN3):c.1063C>T (p.Arg355Trp)

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.1063C>T (p.Arg355Trp)

HGVS:

NC_000015.10:g.42394289C>T
NG_008660.1:g.51187C>T
NM_000070.3:c.1063C>TMANE SELECT
NM_024344.2:c.1063C>T
NM_173087.2:c.919C>T
NP_000061.1:p.Arg355Trp
NP_077320.1:p.Arg355Trp
NP_775110.1:p.Arg307Trp
LRG_849t1:c.1063C>T
LRG_849:g.51187C>T
LRG_849p1:p.Arg355Trp
NC_000015.9:g.42686487C>T
NM_000070.2:c.1063C>T

Protein change:

R307W

Links:

dbSNP: rs749099493

NCBI 1000 Genomes Browser:

rs749099493

Molecular consequence:

NM_000070.3:c.1063C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_024344.2:c.1063C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_173087.2:c.919C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Autosomal recessive limb-girdle muscular dystrophy type 2A (LGMDR1)
Synonyms:: LEYDEN-MOEBIUS MUSCULAR DYSTROPHY; MUSCULAR DYSTROPHY, PELVOFEMORAL; Limb-girdle muscular dystrophy, type 2A; 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
SCV000793223	Counsyl	no assertion criteria provided	Likely pathogenic (Aug 4, 2017)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 17994539, 19364062, 23821418, 18854869, 26404900, 15689361
SCV000840444	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 25, 2017)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 17994539, 15884399, 15689361, 25741868
SCV001200165	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 24, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 15689361, 17236769, 19364062, 23821418, 29970176, 16650086, 28403181, 28492532
SCV001454334	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 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	1	not provided	not provided	1	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

How to tackle the diagnosis of limb-girdle muscular dystrophy 2A.

Fanin M, Nascimbeni AC, Tasca E, Angelini C.

Eur J Hum Genet. 2009 May;17(5):598-603. doi: 10.1038/ejhg.2008.193. Epub 2008 Oct 15.

PubMed [citation]

PMID:: 18854869
PMCID:: PMC2986267

ISPD mutations account for a small proportion of Italian Limb Girdle Muscular Dystrophy cases.

Magri F, Colombo I, Del Bo R, Previtali S, Brusa R, Ciscato P, Scarlato M, Ronchi D, D'Angelo MG, Corti S, Moggio M, Bresolin N, Comi GP.

BMC Neurol. 2015 Sep 24;15:172. doi: 10.1186/s12883-015-0428-8.

PubMed [citation]

PMID:: 26404900
PMCID:: PMC4582941

See all PubMed Citations (13)

Details of each submission

From Counsyl, SCV000793223.3

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

Description

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

#	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 Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota, SCV000840444.1

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

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001200165.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 355 of the CAPN3 protein (p.Arg355Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 15689361, 17236769, 19364062, 23821418, 29970176). ClinVar contains an entry for this variant (Variation ID: 281254). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CAPN3 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg355 amino acid residue in CAPN3. Other variant(s) that disrupt this residue have been observed in individuals with CAPN3-related conditions (PMID: 16650086, 28403181), which suggests that this may be a clinically significant amino acid residue. 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., SCV001454334.1

#	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: Jul 13, 2025

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