rs371859345

Positions:

chr14-23402697-A-T

Variant summary

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

The NM_002471.4(MYH6):c.1002T>A(p.Asp334Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,144 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000073 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

MYH6
NM_002471.4 missense, splice_region

Scores

Splicing: ADA: 0.00004650

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 1.11

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:

MYH6 (HGNC:):

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 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.

BS2

High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH6	NM_002471.4 linkuse as main transcript	c.1002T>A	p.Asp334Glu	missense_variant, splice_region_variant	11/39	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.1002T>A	p.Asp334Glu	missense_variant, splice_region_variant	11/39	5	NM_002471.4	ENSP00000386041.3		P13533
MYH6	ENST00000557461.2 linkuse as main transcript	n.1069T>A		splice_region_variant, non_coding_transcript_exon_variant	11/14	5

Frequencies

GnomAD3 genomes

AF:

0.0000727

AC:

AN:

151276

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000267

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251258

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135820

show subpopulations

Gnomad AFR exome

AF:

0.000492

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461752

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727170

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.0000224

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

AF:

0.0000727

AC:

AN:

151392

Hom.:

Cov.:

AF XY:

0.0000541

AC XY:

AN XY:

73936

show subpopulations

Gnomad4 AFR

AF:

0.000266

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000793

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 12, 2015	The p.Asp334Glu variant in MYH6 has not been previously reported in individuals with cardiomyopathy, but has been identified in 2/10340 African chromosomes by t he Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs3 71859345). Computational prediction tools and conservation analysis do not provi de strong support for or against and impact to the protein. This variant is loca ted in the last three bases of the exon, which is part of the 5? splice region; however, computational tools do not suggest an impact to splicing. This informat ion is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Asp334Glu variant is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 05, 2022	- -

Hypertrophic cardiomyopathy 14

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 28, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 334 of the MYH6 protein (p.Asp334Glu). This variant is present in population databases (rs371859345, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with MYH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 228883). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 11, 2022

Reported in association with HCM in published literature (Ingles 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: 30681346) -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 02, 2024

The p.D334E variant (also known as c.1002T>A), located in coding exon 9 of the MYH6 gene, results from a T to A substitution at nucleotide position 1002. The aspartic acid at codon 334 is replaced by glutamic acid, an amino acid with highly similar properties. 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 alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Benign

-0.086

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.74

D;D

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.36

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.86

D;.

M_CAP

Benign

0.084

MetaRNN

Uncertain

0.73

D;D

MetaSVM

Uncertain

-0.13

MutationAssessor

Uncertain

2.0

M;M

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.0

D;D

REVEL

Uncertain

0.61

Sift

Benign

0.065

T;T

Sift4G

Benign

0.12

T;T

Polyphen

0.14

B;B

Vest4

0.72

MutPred

0.61

Gain of catalytic residue at F337 (P = 0.0134);Gain of catalytic residue at F337 (P = 0.0134);

MVP

0.89

MPC

0.47

ClinPred

0.15

GERP RS

1.8

Varity_R

0.20

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000047

dbscSNV1_RF

Benign

0.042

SpliceAI score (max)

0.010

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