NM_000070.3(CAPN3):c.1657G>A (p.Glu553Lys) AND Autosomal recessive limb-girdle muscular dystrophy type 2A

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jul 26, 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:: RCV000668383.8

Allele description [Variation Report for NM_000070.3(CAPN3):c.1657G>A (p.Glu553Lys)]

NM_000070.3(CAPN3):c.1657G>A (p.Glu553Lys)

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.1657G>A (p.Glu553Lys)

HGVS:

NC_000015.10:g.42402914G>A
NG_008660.1:g.59812G>A
NM_000070.3:c.1657G>AMANE SELECT
NM_024344.2:c.1657G>A
NM_173087.2:c.1513G>A
NM_173088.2:c.121G>A
NP_000061.1:p.Glu553Lys
NP_077320.1:p.Glu553Lys
NP_775110.1:p.Glu505Lys
NP_775111.1:p.Glu41Lys
LRG_849t1:c.1657G>A
LRG_849:g.59812G>A
LRG_849p1:p.Glu553Lys
NC_000015.9:g.42695112G>A
NM_000070.2:c.1657G>A

Protein change:

E41K

Links:

dbSNP: rs767739787

NCBI 1000 Genomes Browser:

rs767739787

Molecular consequence:

NM_000070.3:c.1657G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_024344.2:c.1657G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_173087.2:c.1513G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_173088.2:c.121G>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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Chain A, NAD-dependent alcohol dehydrogenase
Chain A, NAD-dependent alcohol dehydrogenase
gi|34810239|pdb|1NVG|A

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000792974	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Jul 25, 2017)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21204801, 11731278, 15689361 Citation Link,
SCV000935890	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 26, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 11731278, 15689361, 20044116, 21204801, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000792974

Counsyl

criteria provided, single submitter

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

Likely pathogenic
(Jul 25, 2017)

unknown

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV000935890

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 26, 2023)

germline

clinical testing

PubMed (5)
[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	unknown	unknown	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

Citations

PubMed

Myopathy with lobulated muscle fibers: evidence for heterogeneous etiology and clinical presentation.

Figarella-Branger D, El-Dassouki M, Saenz A, Cobo AM, Malzac P, Tong S, Cassotte E, Azulay JP, Pouget J, Pellissier JF.

Neuromuscul Disord. 2002 Jan;12(1):4-12.

PubMed [citation]

PMID:: 11731278

LGMD2A: genotype-phenotype correlations based on a large mutational survey on the calpain 3 gene.

Sáenz A, Leturcq F, Cobo AM, Poza JJ, Ferrer X, Otaegui D, Camaño P, Urtasun M, Vílchez J, Gutiérrez-Rivas E, Emparanza J, Merlini L, Paisán C, Goicoechea M, Blázquez L, Eymard B, Lochmuller H, Walter M, Bonnemann C, Figarella-Branger D, Kaplan JC, Urtizberea JA, et al.

Brain. 2005 Apr;128(Pt 4):732-42. Epub 2005 Feb 2.

PubMed [citation]

PMID:: 15689361

See all PubMed Citations (5)

Details of each submission

From Counsyl, SCV000792974.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

#	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, SCV000935890.4

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

Description

This variant is present in population databases (rs767739787, gnomAD 0.0009%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 553 of the CAPN3 protein (p.Glu553Lys). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy type 2A (PMID: 11731278, 15689361, 20044116, 21204801). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. ClinVar contains an entry for this variant (Variation ID: 553020).

#	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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