NM_000070.3(CAPN3):c.2329A>G (p.Ile777Val) AND Limb-girdle muscular dystrophy, type 2A

Clinical significance:Uncertain significance (Last evaluated: Jul 27, 2018)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000644992.4

Allele description [Variation Report for NM_000070.3(CAPN3):c.2329A>G (p.Ile777Val)]

NM_000070.3(CAPN3):c.2329A>G (p.Ile777Val)

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.2329A>G (p.Ile777Val)
HGVS:
  • NC_000015.10:g.42410949A>G
  • NG_008660.1:g.67847A>G
  • NM_000070.3:c.2329A>GMANE SELECT
  • NM_024344.1:c.2311A>G
  • NM_173087.1:c.2053A>G
  • NM_173088.1:c.793A>G
  • NM_173089.1:c.334A>G
  • NM_173090.1:c.334A>G
  • NP_000061.1:p.Ile777Val
  • NP_077320.1:p.Ile771Val
  • NP_775110.1:p.Ile685Val
  • NP_775111.1:p.Ile265Val
  • NP_775112.1:p.Ile112Val
  • NP_775113.1:p.Ile112Val
  • LRG_849t1:c.2329A>G
  • LRG_849:g.67847A>G
  • LRG_849p1:p.Ile777Val
  • NC_000015.9:g.42703147A>G
  • NM_000070.2:c.2329A>G
Protein change:
I112V
Links:
dbSNP: rs149969786
NCBI 1000 Genomes Browser:
rs149969786
Molecular consequence:
  • NM_000070.3:c.2329A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_024344.1:c.2311A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_173087.1:c.2053A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_173088.1:c.793A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_173089.1:c.334A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_173090.1:c.334A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Limb-girdle muscular dystrophy, type 2A (LGMDR1)
Synonyms:
Limb-girdle muscular dystrophy type 2; Muscular dystrophy, pelvofemoral; Leyden-Moebius muscular dystrophy; 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
SCV000766728Invitaecriteria provided, single submitter
Uncertain significance
(Jul 27, 2018)
germlineclinical testing

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

SCV000800486Counsylcriteria provided, single submitter
Uncertain significance
(Jan 3, 2017)
unknownclinical testing

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

Citation Link,

SCV001456377Natera, Inc.no assertion criteria providedUncertain 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

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

A first-line diagnostic assay for limb-girdle muscular dystrophy and other myopathies.

Monies D, Alhindi HN, Almuhaizea MA, Abouelhoda M, Alazami AM, Goljan E, Alyounes B, Jaroudi D, AlIssa A, Alabdulrahman K, Subhani S, El-Kalioby M, Faquih T, Wakil SM, Altassan NA, Meyer BF, Bohlega S.

Hum Genomics. 2016 Sep 27;10(1):32.

PubMed [citation]
PMID:
27671536
PMCID:
PMC5037890

Details of each submission

From Invitae, SCV000766728.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces isoleucine with valine at codon 777 of the CAPN3 protein (p.Ile777Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs149969786, ExAC 0.01%). This variant has been reported in an individual affected with distal posterior limb muscle atrophy and weakness (PMID: 27671536). ClinVar contains an entry for this variant (Variation ID: 191056). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 Counsyl, SCV000800486.1

#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., SCV001456377.1

#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: Aug 27, 2021

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