NM_005159.5(ACTC1):c.268C>T (p.His90Tyr) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 9, 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:: RCV000697168.7

Allele description [Variation Report for NM_005159.5(ACTC1):c.268C>T (p.His90Tyr)]

NM_005159.5(ACTC1):c.268C>T (p.His90Tyr)

Genes:

GJD2-DT:GJD2 divergent transcript [Gene - HGNC]
ACTC1:actin alpha cardiac muscle 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q14

Genomic location:

Preferred name:

NM_005159.5(ACTC1):c.268C>T (p.His90Tyr)

Other names:

p.H90Y:CAC>TAC

HGVS:

NC_000015.10:g.34793431G>A
NG_007553.1:g.7296C>T
NM_005159.5:c.268C>TMANE SELECT
NP_005150.1:p.His90Tyr
LRG_388t1:c.268C>T
LRG_388:g.7296C>T
NC_000015.9:g.35085632G>A
NM_005159.4:c.268C>T
P68032:p.His90Tyr
c.268C>T

Protein change:

H90Y; HIS90TYR

Links:

UniProtKB: P68032#VAR_045924; OMIM: 102540.0004; dbSNP: rs121912676

NCBI 1000 Genomes Browser:

rs121912676

Molecular consequence:

NM_005159.5:c.268C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hypertrophic cardiomyopathy 11
Synonyms:: Familial hypertrophic cardiomyopathy 11; ACTC1-Related Familial Hypertrophic Cardiomyopathy
Identifiers:: MONDO: MONDO:0012799; MedGen: C2677506; OMIM: 612098

Name:: Dilated cardiomyopathy 1R (CMD1R)
Identifiers:: MONDO: MONDO:0013261; MedGen: C3150681; Orphanet: 154; Orphanet: 54260; OMIM: 613424

Name:: Atrial septal defect 5 (ASD5)
Identifiers:: MONDO: MONDO:0013011; MedGen: C2748552; Orphanet: 1478; OMIM: 612794

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Lim2 lens intrinsic membrane protein 2 [Mus musculus]
Lim2 lens intrinsic membrane protein 2 [Mus musculus]
Gene ID:233187

Gene
233187[uid] AND (alive[prop]) (1)
Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000825765	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 9, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 18403758, 27532257, 28356264, 29121657, 30297972, 31481237, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000825765

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 9, 2023)

germline

clinical testing

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

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

Shared genetic causes of cardiac hypertrophy in children and adults.

Morita H, Rehm HL, Menesses A, McDonough B, Roberts AE, Kucherlapati R, Towbin JA, Seidman JG, Seidman CE.

N Engl J Med. 2008 May 1;358(18):1899-908. doi: 10.1056/NEJMoa075463. Epub 2008 Apr 9.

PubMed [citation]

PMID:: 18403758
PMCID:: PMC2752150

Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples.

Walsh R, Thomson KL, Ware JS, Funke BH, Woodley J, McGuire KJ, Mazzarotto F, Blair E, Seller A, Taylor JC, Minikel EV, Exome Aggregation Consortium, MacArthur DG, Farrall M, Cook SA, Watkins H.

Genet Med. 2017 Feb;19(2):192-203. doi: 10.1038/gim.2016.90. Epub 2016 Aug 17.

PubMed [citation]

PMID:: 27532257
PMCID:: PMC5116235

See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000825765.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 90 of the ACTC1 protein (p.His90Tyr). This variant is present in population databases (rs121912676, gnomAD 0.003%). This missense change has been observed in individual(s) with left ventricular hypertrophy or hypertrophic cardiomyopathy (PMID: 18403758, 27532257, 28356264, 29121657, 30297972). ClinVar contains an entry for this variant (Variation ID: 18326). 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 ACTC1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ACTC1 function (PMID: 31481237). 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.

#	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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