NM_000070.3(CAPN3):c.2093G>A (p.Arg698His) AND not specified

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Sep 1, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003387895.1

Allele description [Variation Report for NM_000070.3(CAPN3):c.2093G>A (p.Arg698His)]

NM_000070.3(CAPN3):c.2093G>A (p.Arg698His)

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.2093G>A (p.Arg698His)

HGVS:

NC_000015.10:g.42409973G>A
NG_008660.1:g.66871G>A
NM_000070.3:c.2093G>AMANE SELECT
NM_024344.2:c.2075G>A
NM_173087.2:c.1817G>A
NM_173088.2:c.557G>A
NM_173089.2:c.98G>A
NM_173090.2:c.98G>A
NP_000061.1:p.Arg698His
NP_077320.1:p.Arg692His
NP_775110.1:p.Arg606His
NP_775111.1:p.Arg186His
NP_775112.1:p.Arg33His
NP_775113.1:p.Arg33His
LRG_849t1:c.2093G>A
LRG_849:g.66871G>A
LRG_849p1:p.Arg698His
NC_000015.9:g.42702171G>A
NM_000070.2:c.2093G>A

Protein change:

R186H

Links:

dbSNP: rs190793093

NCBI 1000 Genomes Browser:

rs190793093

Molecular consequence:

NM_000070.3:c.2093G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_024344.2:c.2075G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_173087.2:c.1817G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_173088.2:c.557G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_173089.2:c.98G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_173090.2:c.98G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004099913	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Sep 1, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30564623, 25135358 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004099913

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Sep 1, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

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

Citations

PubMed

Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients.

Nallamilli BRR, Chakravorty S, Kesari A, Tanner A, Ankala A, Schneider T, da Silva C, Beadling R, Alexander JJ, Askree SH, Whitt Z, Bean L, Collins C, Khadilkar S, Gaitonde P, Dastur R, Wicklund M, Mozaffar T, Harms M, Rufibach L, Mittal P, Hegde M.

Ann Clin Transl Neurol. 2018 Dec;5(12):1574-1587. doi: 10.1002/acn3.649.

PubMed [citation]

PMID:: 30564623
PMCID:: PMC6292381

Autosomal recessive limb-girdle muscular dystrophies in the Czech Republic.

Stehlíková K, Skálová D, Zídková J, Mrázová L, Vondráček P, Mazanec R, Voháňka S, Haberlová J, Hermanová M, Zámečník J, Souček O, Ošlejšková H, Dvořáčková N, Solařová P, Fajkusová L.

BMC Neurol. 2014 Aug 19;14:154. doi: 10.1186/s12883-014-0154-7.

PubMed [citation]

PMID:: 25135358
PMCID:: PMC4145250

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004099913.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: CAPN3 c.2093G>A (p.Arg698His) results in a non-conservative amino acid change located in the EF-hand domain (IPR002048) of the encoded protein sequence. This alters a highly conserved amino acid in which other missense changes have been found in association with disease (HGMD), suggesting this may be a clinically important residue. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251334 control chromosomes (gnomAD). c.2093G>A has been reported in the literature in two individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (Stehlikova_2014, Nallamilli_2018), and one was reported as compound heterozygous with a pathogenic variant. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25135358, 30564623). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly 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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