NM_000070.3(CAPN3):c.664G>A (p.Gly222Arg) AND Autosomal recessive limb-girdle muscular dystrophy type 2A

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jul 26, 2022
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:: RCV000672914.6

Allele description [Variation Report for NM_000070.3(CAPN3):c.664G>A (p.Gly222Arg)]

NM_000070.3(CAPN3):c.664G>A (p.Gly222Arg)

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.664G>A (p.Gly222Arg)

HGVS:

NC_000015.10:g.42388959G>A
NG_008660.1:g.45857G>A
NM_000070.3:c.664G>AMANE SELECT
NM_024344.2:c.664G>A
NM_173087.2:c.664G>A
NP_000061.1:p.Gly222Arg
NP_077320.1:p.Gly222Arg
NP_775110.1:p.Gly222Arg
LRG_849t1:c.664G>A
LRG_849:g.45857G>A
LRG_849p1:p.Gly222Arg
NC_000015.9:g.42681157G>A
NM_000070.2:c.664G>A

Protein change:

G222R

Links:

dbSNP: rs1345121557

NCBI 1000 Genomes Browser:

rs1345121557

Molecular consequence:

NM_000070.3:c.664G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_024344.2:c.664G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_173087.2:c.664G>A - 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
SCV000798069	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Feb 21, 2018)	unknown	clinical testing	PubMed (9) [See all records that cite these PMIDs] 16141003, 11371436, 26886200, 16542520, 22006685, 9777948, 25512505, 9762961, 15689361 Citation Link,
SCV002122336	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 26, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 9762961, 16542520, 22006685, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000798069

Counsyl

criteria provided, single submitter

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

Likely pathogenic
(Feb 21, 2018)

unknown

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

Citation Link,

SCV002122336

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 26, 2022)

germline

clinical testing

PubMed (4)
[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

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

Mutations in calpain 3 associated with limb girdle muscular dystrophy: analysis by molecular modeling and by mutation in m-calpain.

Jia Z, Petrounevitch V, Wong A, Moldoveanu T, Davies PL, Elce JS, Beckmann JS.

Biophys J. 2001 Jun;80(6):2590-6.

PubMed [citation]

PMID:: 11371436
PMCID:: PMC1301447

See all PubMed Citations (10)

Details of each submission

From Counsyl, SCV000798069.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

#	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, SCV002122336.3

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

Description

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"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CAPN3 function (PMID: 22006685). ClinVar contains an entry for this variant (Variation ID: 556854). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 9762961, 16542520, 22006685). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 222 of the CAPN3 protein (p.Gly222Arg).

#	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: Mar 16, 2024

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