chr14-23388186-G-T

Variant names:

• chr14-23388186-G-T
• rs727503234
• NM_002471.4:c.4328C>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_002471.4(MYH6):​c.4328C>A​(p.Ala1443Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000203 in 1,612,202 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: MYH6 NM_002471.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:16
• Conservation: PhyloP100: 7.70

Genes affected

MYH6 (HGNC:7576): (myosin heavy chain 6) Cardiac muscle myosin is a hexamer consisting of two heavy chain subunits, two light chain subunits, and two regulatory subunits. This gene encodes the alpha heavy chain subunit of cardiac myosin. The gene is located approximately 4kb downstream of the gene encoding the beta heavy chain subunit of cardiac myosin. Mutations in this gene cause familial hypertrophic cardiomyopathy and atrial septal defect 3. [provided by RefSeq, Feb 2017]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd4 at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH6	NM_002471.4	c.4328C>A	p.Ala1443Asp	missense_variant	Exon 30 of 39	ENST00000405093.9	NP_002462.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH6	ENST00000405093.9	c.4328C>A	p.Ala1443Asp	missense_variant	Exon 30 of 39	5	NM_002471.4	ENSP00000386041.3

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000323

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000835 AC: 21 AN: 251422 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135888

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000206 AC: 301 AN: 1459992 Hom.: 0 Cov.: 35 AF XY: 0.000191 AC XY: 139 AN XY: 726306

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

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: 0.000263

Gnomad4 OTH exome AF: 0.0000996

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74352

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000128 Hom.: 0

Bravo AF: 0.000132

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:6

Apr 07, 2022

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 25, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in individuals with various forms of cardiac disease, including congenital heart defects, atrial fibrillation, and cardiomyopathies (Granados-Riveron et al., 2010; Granados-Riveron et al., 2012; Gonzalez-Garay et al., 2013; Tomita-Mitchell et al., 2016; Dal Ferro et al., 2017; Gigli et al., 2019; Marschall et al., 2019; Robyns et al., 2020; Verdonschot et al., 2020; Bowling et al., 2022; Zhu et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28416588, 20656787, 27789736, 29875424, 31514951, 32880476, 35456442, 31513939, 31737537, 22011241, 34930662, 24082139) -

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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Uncertain:2

Nov 01, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Ala1443Asp variant in MYH6 has been reported in 1 individual with congenital heart disease (ASD) and was absent from at least 960 control chromosomes (Grana dos-Riveron 2010, Granados-Riveron 2012). It was also absent from large populati on studies. Computational analyses (biochemical amino acid properties, conservat ion, AlignGVGD, PolyPhen2, and SIFT) suggest that this variant may impact the pr otein, though this information is not predictive enough to determine pathogenici ty. In summary, additional information is needed to fully assess the clinical si gnificance of this variant. -

Jan 30, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MYH6 c.4328C>A (p.Ala1443Asp) results in a non-conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 251422 control chromosomes (gnomAD). The observed variant frequency is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH6 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. c.4328C>A has been reported in the literature in individuals affected or suspected with Cardiomyopathy (examples: Gonzalez_2013, Dal ferro_2017, Gigli_2019, Mazzarotto_2019, Marschall_2019, Verdonschot_2020), Congenital heart defects (Granados-Riveron_2010), atrial septal defects (Bowling_2022) and Hypoplastic left heart syndrome (Tomita-Mitchell_2016, Najib_ 2023). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. The following publications have been ascertained in the context of this evaluation (PMID: 34930662, 28416588, 31514951, 24082139, 22011241, 31737537, 29875424, 36890431, 31513939, 27789736, 32880476, 35456442). ClinVar contains an entry for this variant (Variation ID: 164221). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Atrial septal defect 3 Uncertain:2

Jul 12, 2018

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

ACMG codes: PP3 -

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2, v3) <0.001 for a dominant condition (26 heterozygotes, 0 homozygotes). (SP) 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 myosin tail domain (NCBI). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported many times as a VUS within European cohorts (ClinVar, LOVD, cardiodb, PMID: 30847666, PMID: 29875424). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Hypertrophic cardiomyopathy 14 Uncertain:1

Jan 26, 2025

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 aspartic acid, which is acidic and polar, at codon 1443 of the MYH6 protein (p.Ala1443Asp). This variant is present in population databases (rs727503234, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of MYH6-related conditions (PMID: 20656787, 24082139, 27789736, 28416588, 29875424, 31513939, 31737537, 32880476, 36890431). ClinVar contains an entry for this variant (Variation ID: 164221). 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 MYH6 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. -

Dilated cardiomyopathy 1EE;C2750467:Hypertrophic cardiomyopathy 14;C3279790:Atrial septal defect 3;C3279791:Sick sinus syndrome 3, susceptibility to;C3495498:Hypertrophic cardiomyopathy 1 Uncertain:1

Sep 09, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary dilated cardiomyopathy Uncertain:1

Sep 29, 2014

Blueprint Genetics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Primary familial hypertrophic cardiomyopathy Uncertain:1

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Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy Uncertain:1

Oct 31, 2018

Center for Human Genetics, University of Leuven

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Uncertain:1

Jul 07, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A1443D variant (also known as c.4328C>A), located in coding exon 28 of the MYH6 gene, results from a C to A substitution at nucleotide position 4328. The alanine at codon 1443 is replaced by aspartic acid, an amino acid with dissimilar properties. This alteration has been reported in various cohorts, including those with hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), congenital heart defects (including a hypoplastic left heart syndrome (HLHS) cohort), as well as in a cohort of volunteers who underwent exome sequencing; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301; Dal Ferro M et al. Heart, 2017 11;103:1704-1710; Tomita-Mitchell A et al. Physiol. Genomics, 2016 12;48:912-921; Granados-Riveron JT et al. Congenit Heart Dis Oct;7:151-9; Gonzalez-Garay ML et al. Proc. Natl. Acad. Sci. U.S.A., 2013 Oct;110:16957-62; Mazzarotto F et al. Genet. Med., 2019 02;21:284-292; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;D
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;.
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.55	D;D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Uncertain	2.5	M;M
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0040	D;D
Sift4G	Benign	0.29	T;T
Polyphen		0.94	P;P
Vest4		0.53
MVP		0.97
MPC		1.0
ClinPred		0.58	D
GERP RS		4.6
Varity_R		0.66
gMVP		0.72

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

Other links and lift over

dbSNP: rs727503234; hg19: chr14-23857395;