rs140660481

Positions:

chr14-23403415-C-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4BP6BS2

The NM_002471.4(MYH6):c.831G>T(p.Gln277His) variant causes a missense change. The variant allele was found at a frequency of 0.000259 in 1,613,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00026 ( 0 hom. )

Consequence

MYH6
NM_002471.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:7

Conservation

PhyloP100: 3.87

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 -5 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.37231016).

BP6

Variant 14-23403415-C-A is Benign according to our data. Variant chr14-23403415-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 177985.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=5, Benign=1}. Variant chr14-23403415-C-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 41 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH6	NM_002471.4 linkuse as main transcript	c.831G>T	p.Gln277His	missense_variant	10/39	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.831G>T	p.Gln277His	missense_variant	10/39	5	NM_002471.4	ENSP00000386041.3		P13533
MYH6	ENST00000557461.2 linkuse as main transcript	n.898G>T		non_coding_transcript_exon_variant	10/14	5

Frequencies

GnomAD3 genomes

AF:

0.000276

AC:

AN:

152000

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000456

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.000398

AC:

100

AN:

251478

Hom.:

AF XY:

0.000397

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00142

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000360

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.000258

AC:

377

AN:

1461874

Hom.:

Cov.:

AF XY:

0.000252

AC XY:

183

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00125

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000242

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.000270

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000456

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.000400

Hom.:

Bravo

AF:

0.000295

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000420

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 19, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 26, 2019	The MYH6 c.831G>T; p.Gln277His variant (rs140660481) is reported in the literature in individuals affected with congenital heart defects but not in individuals with dilated cardiomyopathy (Tomita-Mitchell 2016 and Pulignani 2018). However, this variant is also found in the Latino population with an allele frequency of 0.14 % (50 / 35,424 alleles) in the Genome Aggregation Database. This variant is reported as likely benign and VUS in ClinVar (Variation ID: 177985). The glutamine at codon 277 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict conflicting effects of this variant on protein structure/function. However, given the lack of clinical data in syndromes typically associated with MYH6 variants and functional data, the significance of the p.Gln277His variant is uncertain at this time. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 22, 2019	This variant is associated with the following publications: (PMID: 23861362, 27789736, 29332214, 32880476) -
Uncertain significance, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 13, 2019	The p.Gln277His variant in MYH6 is classified as likely benign because it has been identified in 0.14% (50/35424) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BS1 -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 17, 2020	Variant summary: MYH6 c.831G>T (p.Gln277His) results in a non-conservative amino acid change located in the Myosin head, motor domain 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 0.0004 in 251478 control chromosomes, predominantly at a frequency of 0.0014 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 56 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 Latino origin. c.831G>T has been reported in the literature in individuals affected with Cardiomyopathy and Hypoplastic left heart syndrome (Ng_2013, Tomita-Mitchell_2016, Pulignani_2018, Westphal_2019, Martinez-Matilla_2019). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (3x) and likely benign (3x). Based on the evidence outlined above, the variant was classified as likely benign. -

Long QT syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Dept of Medical Biology, Uskudar University

Jan 08, 2024

Criteria: BS1, PP3 -

Hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics

- -

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

- -

Hypertrophic cardiomyopathy 14

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 20, 2024

- -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Aug 06, 2021

- -

Hypertrophic cardiomyopathy;C1142166:Brugada syndrome;C4021133:Left ventricular noncompaction cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Jun 05, 2018

MYH6 Gln277His has been identified in 2 HCM, 1 LVNC and 1 Brugada syndrome proband from our research program. This variant has been found in the Genome Aggregation Database (http://gnomad.broadinstitute.org/)at an allele frequency of 0.00037, which is higher then expected for any these inherited heart condition. Considering the variable phenotypes and population frequency we classify this variant as 'likely benign'. -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 29, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Benign

-0.090

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.84

D;D

Eigen

Benign

-0.027

Eigen_PC

Benign

-0.036

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

D;.

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.37

T;T

MetaSVM

Uncertain

0.039

MutationAssessor

Uncertain

2.7

M;M

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-4.0

D;D

REVEL

Uncertain

0.63

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.0030

B;B

Vest4

0.88

MutPred

0.86

Gain of catalytic residue at A280 (P = 0.0181);Gain of catalytic residue at A280 (P = 0.0181);

MVP

0.72

MPC

0.41

ClinPred

0.14

GERP RS

3.7

Varity_R

0.89

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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