14-23405680-C-T

Position:

chr14-23405680-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PP2PP3_ModerateBP6BS2

The NM_002471.4(MYH6):c.292G>A(p.Glu98Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000637 in 1,614,186 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00031 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00067 ( 1 hom. )

Consequence

MYH6
NM_002471.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11B:2

Conservation

PhyloP100: 7.77

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 -2 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYH6. . Gene score misZ 0.85843 (greater than the threshold 3.09). Trascript score misZ 4.1282 (greater than threshold 3.09). GenCC has associacion of gene with dilated cardiomyopathy, hypertrophic cardiomyopathy, Keppen-Lubinsky syndrome, atrial septal defect 3, familial isolated dilated cardiomyopathy, hypertrophic cardiomyopathy 14.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.859

BP6

Variant 14-23405680-C-T is Benign according to our data. Variant chr14-23405680-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44474.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=10}. Variant chr14-23405680-C-T is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 47 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH6	NM_002471.4 linkuse as main transcript	c.292G>A	p.Glu98Lys	missense_variant	4/39	ENST00000405093.9	NP_002462.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH6	ENST00000405093.9 linkuse as main transcript	c.292G>A	p.Glu98Lys	missense_variant	4/39	5	NM_002471.4	ENSP00000386041	P1
MYH6	ENST00000557461.2 linkuse as main transcript	n.359G>A		non_coding_transcript_exon_variant	4/14	5

Frequencies

GnomAD3 genomes

AF:

0.000315

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000529

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000254

AC:

AN:

251480

Hom.:

AF XY:

0.000206

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000475

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000671

AC:

981

AN:

1461894

Hom.:

Cov.:

AF XY:

0.000606

AC XY:

441

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000844

Gnomad4 OTH exome

AF:

0.000430

GnomAD4 genome

AF:

0.000309

AC:

AN:

152292

Hom.:

Cov.:

AF XY:

0.000295

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000529

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000612

Hom.:

Bravo

AF:

0.000321

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000231

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 20, 2023	Reported in individuals with cardiomyopathy (HCM and DCM) or congenital heart defects, though also present in at least one control individual (Granados-Riveron et al., 2010; Haas et al., 2015; Lopes et al., 2015; Jin et al., 2017; Mademont-Soler et al., 2017; Mendes de Almeida et al., 2017; Theis et al., 2021); 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: 28771489, 20656787, 25351510, 28991257, 25163546, 33325730, 28797094, 37194601, 22194935, 35621855, 31376648) -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jun 15, 2020	- -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Sep 22, 2017	Given that this variant has not segregated with disease (a congenital heart defect) in a family and its high minor allele frequency in population databases, we consider this variant a variant of uncertain significance, likely benign and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). There is weak case data. This variant has been seen in at least 3 cases of complex heart defect and an individual with obstructive HCM plus Wolff-Parkinson-White syndrome. The variant did not segregate in a family with a complex heart defect. It was also present in controls. This variant is present in ClinVar. It has been reported by 3 labs, all of which classify it as a variant of uncertain significance. This variant has been reported by Illumina Clinical Services Laboratory. Ambry has seen this variant in one individual. The Laboratory for Molecular Medicine has seen this variant in 2 individuals from 2 families: in 1 adult with obstructive HCM with WPW, and in 1 child with a complex heart defect (an affected relative was negative). Therefore this variant did not segregate with the congenital heart defect. This variant has been reported in Granados-Riveron et al 2010 in both their cohort of patients with congenital heart defects as well as controls. According to the test report, "Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0")." The glutamic acid at codon 98 is conserved across species, as are neighboring amino acids. This variant is present in 58 out of 123,129 individuals listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. Specifically, this variant is present in 48 out of 55,853 individuals of European (non-Finnish descent), 4 out of 7,652 individuals of African descent (highest MAF=0.026%), 3 out of 16,791 individuals of Latino descent, 2 out of 8,624 individuals of East Asian descent and 1 out of 15,391 individuals of South Asian descent. This variant is present in a population of 480 controls (Granados-Riveron et al 2010), although it is not clear how many had this variant. The supplementary data is not available for review. -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 31, 2019	proposed classification - variant undergoing re-assessment, contact laboratory -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 08, 2023	Variant summary: MYH6 c.292G>A (p.Glu98Lys) results in a conservative amino acid change located in the Myosin head, motor domain (IPR001609) 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 0.00025 in 251480 control chromosomes (gnomAD), predominantly at a frequency of 0.00047 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 19 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 a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Eleven ClinVar submitters have assessed the variant since 2014: ten have classified the variant as uncertain significance, and one as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Hypertrophic cardiomyopathy 14

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 25, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 98 of the MYH6 protein (p.Glu98Lys). This variant is present in population databases (rs140596256, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with hypertrophic cardiomyopathy or congenital heart disease (PMID: 20656787, 25351510, 28771489, 28797094, 28991257). ClinVar contains an entry for this variant (Variation ID: 44474). 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 expected to disrupt MYH6 protein function with a positive 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. -

Atrial septal defect 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Feb 02, 2022

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, however gain of function is suggested (PMID: 20656787). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance, however this is only in individuals with atrial septal defect (PMID: 22194935). (I) 0115 - Variants in this gene are known to have variable expressivity, however this is only in individuals with atrial septal defect (PMID: 22194935). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (71 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 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 motor head domain (DECIPHER). (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 as likely benign, but more commonly as a VUS in individuals with hypertrophic cardiomyopathy or sudden unexplained death who often had additional VUSs in related genes (ClinVar, LOVD, PMID: 28797094, PMID: 28771489, PMID: 31376648). Additionally, it has been reported in a homozygous individual with Shone complex, mitrial atresia, double outlet right ventricle and coarctation of the aorta (PMID: 28991257), and within a control cohort (PMID: 25163546). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by duo analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Feb 09, 2017

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 17, 2023

The p.E98K variant (also known as c.292G>A), located in coding exon 2 of the MYH6 gene, results from a G to A substitution at nucleotide position 292. The glutamic acid at codon 98 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in subjects with hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), sudden unexplained death and congenital heart disease (Granados-Riveron JT et al. Hum. Mol. Genet., 2010 Oct;19:4007-16; Lopes LR et al. Heart, 2015 Feb;101:294-301; Mademont-Soler I et al. PLoS ONE, 2017 Aug;12:e0181465; Mendes de Almeida R et al. PLoS ONE, 2017 Aug;12:e0182946; Jin SC et al. Nat. Genet., 2017 Nov;49:1593-1601 ;Martinez-Matilla M et al. Forensic Sci Int Genet, 2019 09;42:203-212; Theis JL et al. Circ Genom Precis Med, 2021 Feb;14:e003126). This amino acid position is highly 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. -

Hypertrophic cardiomyopathy 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Dec 10, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

D;D

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;.

M_CAP

Pathogenic

0.30

MetaRNN

Pathogenic

0.86

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

H;H

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-3.1

D;D

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

0.98

D;D

Vest4

0.96

MVP

0.97

MPC

1.1

ClinPred

0.35

GERP RS

3.9

Varity_R

0.84

gMVP

0.97

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