NM_000070.3(CAPN3):c.2105C>T (p.Ala702Val) AND Autosomal recessive limb-girdle muscular dystrophy type 2A

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jan 3, 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:: RCV000311834.8

Allele description [Variation Report for NM_000070.3(CAPN3):c.2105C>T (p.Ala702Val)]

NM_000070.3(CAPN3):c.2105C>T (p.Ala702Val)

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.2105C>T (p.Ala702Val)

HGVS:

NC_000015.10:g.42409985C>T
NG_008660.1:g.66883C>T
NM_000070.3:c.2105C>TMANE SELECT
NM_024344.2:c.2087C>T
NM_173087.2:c.1829C>T
NM_173088.2:c.569C>T
NM_173089.2:c.110C>T
NM_173090.2:c.110C>T
NP_000061.1:p.Ala702Val
NP_077320.1:p.Ala696Val
NP_775110.1:p.Ala610Val
NP_775111.1:p.Ala190Val
NP_775112.1:p.Ala37Val
NP_775113.1:p.Ala37Val
LRG_849t1:c.2105C>T
LRG_849:g.66883C>T
LRG_849p1:p.Ala702Val
NC_000015.9:g.42702183C>T
NM_000070.2:c.2105C>T
P20807:p.Ala702Val

Protein change:

A190V

Links:

UniProtKB: P20807#VAR_009594; dbSNP: rs886042557

NCBI 1000 Genomes Browser:

rs886042557

Molecular consequence:

NM_000070.3:c.2105C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_024344.2:c.2087C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_173087.2:c.1829C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_173088.2:c.569C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_173089.2:c.110C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_173090.2:c.110C>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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GLT8D2 [Coturnix japonica]
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000794103	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Sep 13, 2017)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 16141003, 17236769, 27262448, 19556129, 17994539, 9150160 Citation Link,
SCV001394807	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 3, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 9150160, 16141003, 17236769, 27234031, 27262448, 30056071, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000794103

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))

Likely pathogenic
(Sep 13, 2017)

unknown

clinical testing

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

Citation Link,

SCV001394807

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 3, 2024)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

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

Immunohistochemical analysis of calpain 3: advantages and limitations in diagnosing LGMD2A.

Charlton R, Henderson M, Richards J, Hudson J, Straub V, Bushby K, Barresi R.

Neuromuscul Disord. 2009 Jul;19(7):449-57. doi: 10.1016/j.nmd.2009.05.005. Epub 2009 Jun 24.

PubMed [citation]

PMID:: 19556129

Clinical, molecular, and protein correlations in a large sample of genetically diagnosed Italian limb girdle muscular dystrophy patients.

Guglieri M, Magri F, D'Angelo MG, Prelle A, Morandi L, Rodolico C, Cagliani R, Mora M, Fortunato F, Bordoni A, Del Bo R, Ghezzi S, Pagliarani S, Lucchiari S, Salani S, Zecca C, Lamperti C, Ronchi D, Aguennouz M, Ciscato P, Di Blasi C, Ruggieri A, et al.

Hum Mutat. 2008 Feb;29(2):258-66.

PubMed [citation]

PMID:: 17994539

See all PubMed Citations (9)

Details of each submission

From Counsyl, SCV000794103.1

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

#	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, SCV001394807.5

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

Description

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 702 of the CAPN3 protein (p.Ala702Val). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 9150160, 16141003, 17236769, 27234031, 27262448, 30056071). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 283099). 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 not expected to disrupt CAPN3 protein function with a negative 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

Last Updated: Sep 29, 2024

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