rs397517072

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP2PP3

The NM_005159.5(ACTC1):​c.83C>T​(p.Ala28Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A28T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

ACTC1
NM_005159.5 missense

Scores

12
4
3

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 9.93
Variant links:
Genes affected
ACTC1 (HGNC:143): (actin alpha cardiac muscle 1) Actins are highly conserved proteins that are involved in various types of cell motility. Polymerization of globular actin (G-actin) leads to a structural filament (F-actin) in the form of a two-stranded helix. Each actin can bind to four others. The protein encoded by this gene belongs to the actin family which is comprised of three main groups of actin isoforms, alpha, beta, and gamma. The alpha actins are found in muscle tissues and are a major constituent of the contractile apparatus. Defects in this gene have been associated with idiopathic dilated cardiomyopathy (IDC) and familial hypertrophic cardiomyopathy (FHC). [provided by RefSeq, Jul 2008]
GJD2-DT (HGNC:55560): (GJD2 divergent transcript)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_005159.5
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the ACTC1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 15 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: 4.5244 (above the threshold of 3.09). Trascript score misZ: 6.3156 (above the threshold of 3.09). GenCC associations: The gene is linked to dilated cardiomyopathy, hypertrophic cardiomyopathy, atrial septal defect 5, arrhythmogenic right ventricular cardiomyopathy, familial isolated dilated cardiomyopathy, dilated cardiomyopathy 1R, hypertrophic cardiomyopathy 11.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.776

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ACTC1NM_005159.5 linkc.83C>T p.Ala28Val missense_variant Exon 2 of 7 ENST00000290378.6 NP_005150.1 P68032B3KPP5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ACTC1ENST00000290378.6 linkc.83C>T p.Ala28Val missense_variant Exon 2 of 7 1 NM_005159.5 ENSP00000290378.4 P68032
ACTC1ENST00000560563.2 linkn.189C>T non_coding_transcript_exon_variant Exon 2 of 6 2
GJD2-DTENST00000503496.6 linkn.300-15770G>A intron_variant Intron 2 of 2 2
GJD2-DTENST00000671663.1 linkn.95-15770G>A intron_variant Intron 1 of 1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1460966
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
726816
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Nov 23, 2012
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The Ala28Val variant in ACTC has not been reported in the literature nor detecte d in large and broad populations (European and African American) sequenced by th e NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/), but has be en previously identified in one individual with HCM by our laboratory (unpublish ed data). Computational analyses (biochemical amino acid properties, conservatio n, AlignGVGD, PolyPhen2, and SIFT) suggest that the Ala28Val variant may impact the protein, though this information is not predictive enough to determine patho genicity. Additional information is needed to fully assess the clinical signific ance of the Ala28Val variant. -

Hypertrophic cardiomyopathy 11;C2748552:Atrial septal defect 5;C3150681:Dilated cardiomyopathy 1R Uncertain:1
Oct 16, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 28 of the ACTC1 protein (p.Ala28Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257; internal data). ClinVar contains an entry for this variant (Variation ID: 50937). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ACTC1 protein function with a negative predictive value of 80%. 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. -

not provided Uncertain:1
Mar 06, 2025
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 25611685, 37652022) -

Cardiovascular phenotype Uncertain:1
Aug 14, 2019
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.83C>T (p.A28V) alteration is located in exon 2 (coding exon 1) of the ACTC1 gene. This alteration results from a C to T substitution at nucleotide position 83, causing the alanine (A) at amino acid position 28 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
CardioboostCm
Uncertain
0.79
BayesDel_addAF
Pathogenic
0.29
D
BayesDel_noAF
Pathogenic
0.17
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.85
D
Eigen
Pathogenic
0.72
Eigen_PC
Pathogenic
0.67
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.83
T
M_CAP
Pathogenic
0.64
D
MetaRNN
Pathogenic
0.78
D
MetaSVM
Pathogenic
0.86
D
MutationAssessor
Uncertain
2.4
M
PrimateAI
Pathogenic
0.88
D
PROVEAN
Benign
-1.9
N
REVEL
Pathogenic
0.80
Sift4G
Uncertain
0.036
D
Polyphen
0.91
P
Vest4
0.47
MutPred
0.81
Loss of sheet (P = 0.0817);
MVP
0.99
MPC
2.6
ClinPred
0.99
D
GERP RS
4.2
Varity_R
0.77
gMVP
0.93

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs397517072; hg19: chr15-35086927; COSMIC: COSV51759700; COSMIC: COSV51759700; API