NM_000070.3(CAPN3):c.1714C>T (p.Arg572Trp) AND Autosomal recessive limb-girdle muscular dystrophy type 2A

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Sep 27, 2023
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:: RCV000201202.14

Allele description [Variation Report for NM_000070.3(CAPN3):c.1714C>T (p.Arg572Trp)]

NM_000070.3(CAPN3):c.1714C>T (p.Arg572Trp)

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.1714C>T (p.Arg572Trp)

HGVS:

NC_000015.10:g.42402971C>T
NG_008660.1:g.59869C>T
NM_000070.3:c.1714C>TMANE SELECT
NM_024344.2:c.1714C>T
NM_173087.2:c.1570C>T
NM_173088.2:c.178C>T
NP_000061.1:p.Arg572Trp
NP_077320.1:p.Arg572Trp
NP_775110.1:p.Arg524Trp
NP_775111.1:p.Arg60Trp
LRG_849t1:c.1714C>T
LRG_849:g.59869C>T
LRG_849p1:p.Arg572Trp
NC_000015.9:g.42695169C>T
NM_000070.2:c.1714C>T
P20807:p.Arg572Trp

Protein change:

R524W

Links:

UniProtKB: P20807#VAR_009590; dbSNP: rs863224959

NCBI 1000 Genomes Browser:

rs863224959

Molecular consequence:

NM_000070.3:c.1714C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_024344.2:c.1714C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_173087.2:c.1570C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_173088.2:c.178C>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
SCV000255656	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Dec 31, 2012)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 10330340, 12461690, 15221789, 9150160, 26467025
SCV000791069	Counsyl	no assertion criteria provided	Pathogenic (Apr 21, 2017)	unknown	clinical testing	PubMed (7) [See all records that cite these PMIDs] 12461690, 16650086, 10330340, 18854869, 18563459, 27234031, 17979987
SCV000949407	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 27, 2023)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 9150160, 12461690, 18854869, 27234031, 7720071, 9642272, 10102422, 16650086, 27066545, 27708273, 28492532
SCV001163396	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002085535	Natera, Inc.	no assertion criteria provided	Pathogenic (Jul 17, 2020)	germline	clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
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

Molecular diagnosis in LGMD2A: mutation analysis or protein testing?

Fanin M, Fulizio L, Nascimbeni AC, Spinazzi M, Piluso G, Ventriglia VM, Ruzza G, Siciliano G, Trevisan CP, Politano L, Nigro V, Angelini C.

Hum Mutat. 2004 Jul;24(1):52-62.

PubMed [citation]

PMID:: 15221789

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, Bright AR, Previte D, Zhang K, Rowland CM, McCarthy M, Lapierre JL, Dubois F, Medeiros KA, Batish SD, Jones J, Liaquat K, Hoffman CA, Jaremko M, Wang Z, Sun W, Buller-Burckle A, et al.

Hum Mutat. 2016 Jan;37(1):127-34. doi: 10.1002/humu.22918. Epub 2015 Oct 29.

PubMed [citation]

PMID:: 26467025
PMCID:: PMC4737317

See all PubMed Citations (17)

Details of each submission

From Athena Diagnostics, SCV000255656.2

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Counsyl, SCV000791069.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

#	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 Invitae, SCV000949407.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

This missense change has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 9150160, 12461690, 16650086, 18854869, 27234031). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 572 of the CAPN3 protein (p.Arg572Trp). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg572 amino acid residue in CAPN3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7720071, 9642272, 10102422, 16650086, 27066545, 27708273). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 217152).

#	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 Baylor Genetics, SCV001163396.1

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV002085535.1

#	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: Aug 4, 2024

ClinVar

Relating variation to medicine