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NM_001103.4(ACTN2):c.2551C>T (p.Arg851Cys) AND Dilated cardiomyopathy 1AA

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
May 6, 2021
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:
RCV002470854.2

Allele description [Variation Report for NM_001103.4(ACTN2):c.2551C>T (p.Arg851Cys)]

NM_001103.4(ACTN2):c.2551C>T (p.Arg851Cys)

Gene:
ACTN2:actinin alpha 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1q43
Genomic location:
Preferred name:
NM_001103.4(ACTN2):c.2551C>T (p.Arg851Cys)
HGVS:
  • NC_000001.11:g.236762485C>T
  • NG_009081.2:g.103345C>T
  • NM_001103.4:c.2551C>TMANE SELECT
  • NM_001278343.2:c.2551C>T
  • NM_001278344.2:c.1927C>T
  • NP_001094.1:p.Arg851Cys
  • NP_001094.1:p.Arg851Cys
  • NP_001265272.1:p.Arg851Cys
  • NP_001265273.1:p.Arg643Cys
  • LRG_436t1:c.2551C>T
  • LRG_436:g.103345C>T
  • LRG_436p1:p.Arg851Cys
  • NC_000001.10:g.236925785C>T
  • NG_009081.1:g.81016C>T
  • NM_001103.2:c.2551C>T
  • NM_001103.3:c.2551C>T
Protein change:
R643C
Links:
dbSNP: rs141563497
NCBI 1000 Genomes Browser:
rs141563497
Molecular consequence:
  • NM_001103.4:c.2551C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001278343.2:c.2551C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001278344.2:c.1927C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Dilated cardiomyopathy 1AA (CMD1AA)
Synonyms:
CARDIOMYOPATHY, DILATED, 1AA, WITH OR WITHOUT LEFT VENTRICULAR NONCOMPACTION; CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 23, WITH OR WITHOUT LEFT VENTRICULAR NONCOMPACTION
Identifiers:
MONDO: MONDO:0012808; MedGen: C2677338; Orphanet: 154; OMIM: 612158

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002769348Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(May 6, 2021) 		germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Interpreting secondary cardiac disease variants in an exome cohort.

Ng D, Johnston JJ, Teer JK, Singh LN, Peller LC, Wynter JS, Lewis KL, Cooper DN, Stenson PD, Mullikin JC, Biesecker LG; NIH Intramural Sequencing Center (NISC) Comparative Sequencing Program..

Circ Cardiovasc Genet. 2013 Aug;6(4):337-46. doi: 10.1161/CIRCGENETICS.113.000039. Epub 2013 Jul 16.

PubMed [citation]
PMID:
23861362
PMCID:
PMC3887521

Hypertrophic cardiomyopathy mutations in the calponin-homology domain of ACTN2 affect actin binding and cardiomyocyte Z-disc incorporation.

Haywood NJ, Wolny M, Rogers B, Trinh CH, Shuping Y, Edwards TA, Peckham M.

Biochem J. 2016 Aug 15;473(16):2485-93. doi: 10.1042/BCJ20160421. Epub 2016 Jun 10.

PubMed [citation]
PMID:
27287556
PMCID:
PMC4980809
See all PubMed Citations (4)

Details of each submission

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002769348.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with dilated cardiomyopathy, 1AA, with or without LVNC (MIM#612158), hypertrophic cardiomyopathy, 23, with or without LVNC (MIM#612158), congenital myopathy with structured cores and Z-line abnormalities (MIM#618654) and adult onset distal myopathy, 6 (MIM#618655) (PMID: 27287556). (I) 0107 - This gene is known to be associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - Variant is heterozygous. (I) 0310 - Variant is present in gnomAD >=0.001 and <0.01 for a dominant condition (v2: 39 heterozygotes, 0 homozygotes). (I) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (p.(Arg851His): 13 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Ca2+ insensitive EF hand domain (PDB). It should also be noted that this variant is a methylated arginine site and that genetic changes at these sites has been suggested to be associated with cardiac disease (PMID: 27600370). (I) 0710 – Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. The p.(Arg851His) variant has been classified as a VUS by clinical diagnostic laboratories and also reported once as a VUS in the literature (ClinVar; PMID: 23861362) (I). 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been classified as a VUS by clinical diagnostic laboratories (ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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

Last Updated: Sep 29, 2024