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NM_000070.3(CAPN3):c.2093G>A (p.Arg698His) AND Autosomal recessive limb-girdle muscular dystrophy type 2A

Germline classification:
Uncertain significance (4 submissions)
Last evaluated:
Sep 10, 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:
RCV000644983.7

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)

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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000766713Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Uncertain significance
(Sep 10, 2022)
germlineclinical testing

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

SCV000778587HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-HudsonAlpha
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(Apr 16, 2018)
paternalresearch

PubMed (1)
[See all records that cite this PMID]

SCV000790334Counsyl
criteria provided, single submitter

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))
Uncertain significance
(Mar 15, 2017)
unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV001456369Natera, Inc.
no assertion criteria provided
Uncertain significance
(Sep 16, 2020)
germlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedpaternalyes1not providednot provided1not providedresearch

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

Calpainopathy-a survey of mutations and polymorphisms.

Richard I, Roudaut C, Saenz A, Pogue R, Grimbergen JE, Anderson LV, Beley C, Cobo AM, de Diego C, Eymard B, Gallano P, Ginjaar HB, Lasa A, Pollitt C, Topaloglu H, Urtizberea JA, de Visser M, van der Kooi A, Bushby K, Bakker E, Lopez de Munain A, Fardeau M, et al.

Am J Hum Genet. 1999 Jun;64(6):1524-40.

PubMed [citation]
PMID:
10330340
PMCID:
PMC1377896
See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000766713.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 698 of the CAPN3 protein (p.Arg698His). This variant is present in population databases (rs190793093, gnomAD 0.01%). This missense change has been observed in individual(s) with limb-girdle muscular dystrophy (LGMD) type 2A (PMID: 25135358, 30564623). ClinVar contains an entry for this variant (Variation ID: 499036). 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. This variant disrupts the p.Arg698 amino acid residue in CAPN3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10330340, 15689361, 16411092, 21204801). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

From HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-HudsonAlpha, SCV000778587.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedresearch PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1paternalyes1not providednot provided1not providednot providednot provided

From Counsyl, SCV000790334.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Natera, Inc., SCV001456369.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024