15-34794781-G-T

Variant names:

• chr15-34794781-G-T
• rs397517057
• NM_005159.5:c.28C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_005159.5(ACTC1):​c.28C>A​(p.Leu10Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,613,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L10L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: ACTC1 NM_005159.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:8
• Conservation: PhyloP100: 3.06
• Publications: 5 publications found

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)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.902
• BS2: High AC in GnomAd4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005159.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTC1	NM_005159.5	MANE Select	c.28C>A	p.Leu10Met	missense	Exon 2 of 7	NP_005150.1
	ACTC1	NM_001406482.1		c.28C>A	p.Leu10Met	missense	Exon 1 of 6	NP_001393411.1
	ACTC1	NM_001406483.1		c.28C>A	p.Leu10Met	missense	Exon 2 of 7	NP_001393412.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTC1	ENST00000290378.6	TSL:1 MANE Select	c.28C>A	p.Leu10Met	missense	Exon 2 of 7	ENSP00000290378.4
	ACTC1	ENST00000713613.1		c.28C>A	p.Leu10Met	missense	Exon 2 of 8	ENSP00000518909.1
	ACTC1	ENST00000713610.1		c.28C>A	p.Leu10Met	missense	Exon 2 of 7	ENSP00000518905.1

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152240 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000319 AC: 8 AN: 250682 AF XY: 0.0000369

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000383 AC: 56 AN: 1461346 Hom.: 0 Cov.: 31 AF XY: 0.0000426 AC XY: 31 AN XY: 726964

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.0000895 AC: 4 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53210

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000468 AC: 52 AN: 1111778

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74374

African (AFR) AF: 0.0000241 AC: 1 AN: 41474

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000406 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypertrophic cardiomyopathy 11 Pathogenic:1 Uncertain:1

Jun 08, 2018

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been detected and reported in at least four individuals with hypertrophic cardiomyopathy in the literature (PMID: 22555271, 27532257, 28138913) including an individual with pediatric onset disease (PMID: 22555271). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.003% (8/245,538) and thus is presumed to be rare. The c.28C>A (p.Leu10Met) variant affects a highly conserved amino acid (up to Baker's yeast, considering 12 species) and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.28C>A (p.Leu10Met) variant is classified as likely pathogenic.

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Cardiomyopathy Uncertain:2

Nov 20, 2019

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 20, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces leucine with methionine at codon 10 of the ACTC1 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 22555271, 23054336, 27532257, 28138913, 35026164, 38757491; communication with an external laboratory; ClinVar SCV000676951.5). In one case, this variant was reported in an individual affected with hypertrophic cardiomyopathy and poor clinical course who also carried a pathogenic splice variant in the MYBPC3 gene (PMID: 28138913). This variant has also been reported in a young individual affected with ventricular fibrillation and cardiac arrest (PMID: 31246743). This variant has been identified in 9/282084 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Hypertrophic cardiomyopathy 11;C2748552:Atrial septal defect 5;C3150681:Dilated cardiomyopathy 1R Pathogenic:1

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 10 of the ACTC1 protein (p.Leu10Met). This variant is present in population databases (rs397517057, gnomAD 0.009%). This missense change has been observed in individuals with clinical features of hypertrophic cardiomyopathy (PMID: 2255271, 27532257, 31019026, 37652022; internal data). ClinVar contains an entry for this variant (Variation ID: 50936). 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

not specified Uncertain:1

Jun 28, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Leu10Met variant in ACTC1 has been identified in 3 individuals with HCM (Kindel 2012, Miller 2013, Alejandra 2017, LMM data) and has been identified in 9/282084 chromosomes by gnomAD (http://exac.broadinstitute.org). It has also been reported in ClinVar (Variation ID #50936). Computational prediction tools and conservation analysis do not provide strong evidence for or against an impact to the protien. In summary, the clinical significance of the p.Leu10Met variant is uncertain. ACMG/AMP Criteria applied: PS4_Supporting.

Dilated cardiomyopathy 1R Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

not provided Uncertain:1

Sep 13, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in individuals in association with HCM and cardiomyopathy with ventricular arrhythmia (Kindel et al., 2012; Miller et al., 2013; Walsh et al., 2017; Alejandra Restrepo-Cordoba et al., 2017; Clark et al., 2019); however, no segregation studies were described and one individual with HCM also harbored a splice variant in the MYBPC3 gene; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 23054336, 22555271, 28138913, 31019026)

Hypertrophic cardiomyopathy Uncertain:1

Jul 10, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces leucine with methionine at codon 10 of the ACTC1 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 22555271, 23054336, 27532257, 28138913, 35026164; communication with an external laboratory; ClinVar SCV000676951.5). In one case, this variant was reported in an individual affected with hypertrophic cardiomyopathy and poor clinical course who also carried a pathogenic splice variant in the MYBPC3 gene (PMID: 28138913). This variant has also been reported in a young individual affected with ventricular fibrillation and cardiac arrest (PMID: 31246743). This variant has been identified in 9/282084 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Cardiovascular phenotype Uncertain:1

Dec 18, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.28C>A (p.L10M) alteration is located in exon 2 (coding exon 1) of the ACTC1 gene. This alteration results from a C to A substitution at nucleotide position 28, causing the leucine (L) at amino acid position 10 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
CardioboostCm	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.51
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		3.1
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.59	N
REVEL	Pathogenic	0.77
Sift4G	Uncertain	0.015	D
Polyphen		0.59	P
Vest4		0.87
MutPred		0.68		Gain of catalytic residue at L10 (P = 0.0011)
MVP		1.0
MPC		2.7
ClinPred		0.89	D
GERP RS		3.0
Varity_R		0.69
gMVP		0.93
Mutation Taster		=23/77	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397517057; hg19: chr15-35086982;