14-23388321-C-T

Position:

chr14-23388321-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2

The NM_002471.4(MYH6):c.4193G>A(p.Arg1398Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000575 in 1,613,122 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1398W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00059 ( 2 hom. )

Consequence

MYH6
NM_002471.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:14B:1

Conservation

PhyloP100: 7.60

Variant links:

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]

MYH6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP2

Missense variant where missense usually causes diseases, MYH6

BS2

High AC in GnomAd4 at 63 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH6	NM_002471.4 linkuse as main transcript	c.4193G>A	p.Arg1398Gln	missense_variant	30/39	ENST00000405093.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH6	ENST00000405093.9 linkuse as main transcript	c.4193G>A	p.Arg1398Gln	missense_variant	30/39	5	NM_002471.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000414

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000750

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000386

AC:

AN:

251316

Hom.:

AF XY:

0.000471

AC XY:

AN XY:

135844

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000653

Gnomad FIN exome

AF:

0.0000928

Gnomad NFE exome

AF:

0.000589

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000591

AC:

864

AN:

1460900

Hom.:

Cov.:

AF XY:

0.000588

AC XY:

427

AN XY:

726738

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000754

Gnomad4 FIN exome

AF:

0.0000750

Gnomad4 NFE exome

AF:

0.000680

Gnomad4 OTH exome

AF:

0.000431

GnomAD4 genome

AF:

0.000414

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000828

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000750

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000533

Hom.:

Bravo

AF:

0.000382

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000387

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:14Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:9

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 15, 2023	Reported in association with arrhythmia, sudden death, cardiomyopathy, atrial septal defect, and non-syndromic pulmonary stenosis (Gonzalez-Garay et al., 2013; Blue et al., 2014; Lopes et al., 2015; Bottillo et al., 2016; Hertz et al., 2016; Pulignani et al., 2018; Herkert et al., 2018; Van Lint et al., 2019; Asatryan et al., 2019); 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: 29332214, 23861362, 28087566, 26383259, 25351510, 26350513, 30847666, 25500235, 30975432, 34426522, 29517769, 24082139, 26656175, 35621855) -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 04, 2019	The MYH6 c.4193G>A; p.Arg1398Gln variant (rs150815925) has been identified in at least three patients with some form of cardiomyopathy (Gonzalez-Garay 2013, Bottillo 2016, Pulignani 2018). This variant was also observed in one individual selected from a large cohort not selected for cardiomyopathy, and classified as uncertain based on population frequency (Ng 2013). This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.07 percent in the East Asian population (identified on 20 out of 30,616 chromosomes) and has been reported to the ClinVar database (Variation ID: 191712). The arginine at position 1398 is highly conserved up to Opossum considering 5 species and computational analyses of the effects of the p.Arg1398Gln variant on protein structure and function provides conflicting results (SIFT: damaging, PolyPhen-2: benign). Thus, based on the available information, the clinical significance of this variant is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	MYH6: PS4:Moderate, PP2, PP3, BP5 -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 01, 2015	The p.Arg1398Gln variant in MYH6 has been previously reported in 1 adult with ca rdiac dysrhythmia and 1 unaffected adult with a family history of DCM through a whole exome sequencing study (Gonzalez-Garay 2013). It has also been identified in 36/66590 European chromosomes by the Exome Aggregation Consortium (ExAC, http ://exac.broadinstitute.org; dbSNP rs150815925). Computational prediction tools a nd conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg1398Gln varian t is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 11, 2018	Variant summary: MYH6 c.4193G>A (p.Arg1398Gln) results in a conservative amino acid change located in the Myosin tail (IPR002928) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 277100 control chromosomes (gnomAD and publications). The observed variant frequency is approximately 15-fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH6 causing Cardiomyopathy phenotype (2.5e-05), suggesting that the variant is benign. The variant, c.4193G>A, has been reported in the literature in individuals affected with congenital heart disease and Cardiomyopathy (Bottillo_2015, Gonzalez-Garay_2013, Hertz_2016). Co-occurrences with other pathogenic variant(s) have been reported (MYH7 c.G428A, p.R143Q)(Bottillo_2015), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Hypertrophic cardiomyopathy 14

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1398 of the MYH6 protein (p.Arg1398Gln). This variant is present in population databases (rs150815925, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of MYH6-related conditions (PMID: 24082139, 26383259, 26656175, 29517769, 30847666, 30975432, 36178741). ClinVar contains an entry for this variant (Variation ID: 191712). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYH6 protein function. 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. -

MYH6-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 26, 2023

The MYH6 c.4193G>A variant is predicted to result in the amino acid substitution p.Arg1398Gln. This variant has been reported in an individual with cardiac arrhythmia and an asymptomatic individual with a family history of cardiomyopathy (Table S8/S9 - Gonzalez-Garay et al. 2013. PubMed ID: 24082139). This variant has been reported in multiple individuals with cardiomyopathy (Bottillo et al. 2016. PubMed ID: 26656175; Hertz et al. 2016. PubMed ID: 26383259; Supplemental File 2, van Lint et al. 2019. PubMed ID: 30847666; Table S2, van der Meulen et al. 2022. PubMed ID: 36178741) and in an individual with sudden cardiac arrest (Asatryan et al. 2019. PubMed ID: 30975432). In at least two of these individuals the variant co-occurred with a pathogenic variant in different gene (Bottillo et al. 2016. PubMed ID: 26656175; Asatryan et al. 2019. PubMed ID: 30975432). Additionally, this variant was found in an individual with pulmonary stenosis (Pulignani et al. 2018. PubMed ID: 29332214). This variant is reported in 0.065% of alleles in individuals of South Asian descent in gnomAD and has conflicting interpretations of likely benign and uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/191712/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 06, 2023

The p.R1398Q variant (also known as c.4193G>A), located in coding exon 28 of the MYH6 gene, results from a G to A substitution at nucleotide position 4193. The arginine at codon 1398 is replaced by glutamine, an amino acid with highly similar properties. This variant has co-occurred with variants in other cardiac-related genes in an individual with atrial septal defect (Blue GM et al. J. Am. Coll. Cardiol. 2014 Dec;64(23):2498-506). This variant was detected in an individual reportedly affected with cardiomyopathy and cardiac dysrhythmia and also found in an unaffected individual with family history of cardiomyopathy (Gonzalez-Garay ML et al. Proc. Natl. Acad. Sci. U.S.A., 2013 Oct;110:16957-62). This variant has also been reported in additional hypertrophic and dilated cardiomyopathy cohorts where, in several cases, it co-occurred with other variants in cardiac-related genes (Lopes LR et al. Heart, 2015 Feb;101:294-301; Bottillo I et al. Gene, 2016 Feb;577:227-35; Hertz CL et al. Int J Legal Med. 2016 Jan;130(1):91-102; Herkert JC et al. Genet Med. 2018 11;20(11):1374-1386; Asatryan B et al. Am J Cardiol. 2019 06;123(12):2031-2038). In addition, this variant has been published as a secondary cardiac variant of unknown significance in an exome cohort (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

Cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Mar 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.082

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.66

D;D

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;.

M_CAP

Pathogenic

0.30

MetaRNN

Uncertain

0.56

D;D

MetaSVM

Uncertain

0.17

MutationAssessor

Uncertain

2.2

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-2.8

D;D

REVEL

Uncertain

0.62

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.056

T;T

Polyphen

0.22

B;B

Vest4

0.88

MVP

0.73

MPC

0.39

ClinPred

0.14

GERP RS

4.6

Varity_R

0.47

gMVP

0.52

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over