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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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV004099913Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Uncertain significance
(Sep 1, 2023)
germlineclinical testing

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024