rs145611185

Positions:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP2PP3BP6BS2

The NM_002471.4(MYH6):c.4136C>T(p.Thr1379Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000856 in 1,613,670 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T1379T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00091 ( 2 hom. )

Consequence

MYH6
NM_002471.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:14

Conservation

PhyloP100: 9.65

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 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, 0.778

BP6

Variant 14-23388898-G-A is Benign according to our data. Variant chr14-23388898-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 180425.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Benign=3, Uncertain_significance=1}. Variant chr14-23388898-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 49 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH6	NM_002471.4 linkuse as main transcript	c.4136C>T	p.Thr1379Met	missense_variant	29/39	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.4136C>T	p.Thr1379Met	missense_variant	29/39	5	NM_002471.4	ENSP00000386041	P1

Frequencies

GnomAD3 genomes

AF:

0.000322

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000581

AC:

146

AN:

251472

Hom.:

AF XY:

0.000581

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000173

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00114

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000912

AC:

1333

AN:

1461448

Hom.:

Cov.:

AF XY:

0.000876

AC XY:

637

AN XY:

727034

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.000230

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000936

Gnomad4 NFE exome

AF:

0.00114

Gnomad4 OTH exome

AF:

0.000679

GnomAD4 genome

AF:

0.000322

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000586

Hom.:

Bravo

AF:

0.000487

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.000618

AC:

EpiCase

AF:

0.000981

EpiControl

AF:

0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:14

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:8

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	MYH6: PP3, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 01, 2020	Observed in a family with CHD; however, a nonsense variant in the TBX5 gene was also identified and was found to segregate with disease in this family, while the T1379M variant did not segregate with disease (Blue et al., 2014); Identified in an individual with Brugada syndrome (Hertz et al., 2016); Published in association with autosomal recessive pattern of inheritance in the literature after identifying the T1379M variant in an individual with hypoplastic left heart syndrome who harbored another variant on the opposite MYH6 allele (in trans) (Theis et al. 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar with conflicting classfications (ClinVar Variant ID 180425; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 32880476, 32277046, 30847666, 27789736, 27760138, 26085007, 25500235, 20656787, 25467552) -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 18, 2020	- -

not specified

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 06, 2015	The p.Thr1379Met variant in MYH6 has not been previously reported in individuals with cardiomyopathy, but has been identified in 0.1% (72/66714) of European chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs145611185). Computational prediction tools and conservation analysis suggest that the p.Thr1379Met variant may impact the protein, though this infor mation is not predictive enough to determine pathogenicity. In summary, the clin ical significance of the p.Thr1379Met variant is uncertain. -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Nov 25, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 28, 2019	Variant summary: MYH6 c.4136C>T (p.Thr1379Met) results in a non-conservative amino acid change located in the Myosin tail domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00056 in 277218 control chromosomes, predominantly at a frequency of 0.0011 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 44 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. c.4136C>T has been reported in the literature in affected individuals (Preuss_2016, Tomita-Mitchell_2016, Hertz_2015, Jia_2015, Theis_2015, Blue_2014, Posch_2011) without strong evidence of causality while, it was documented to not co-segregate with disease (Theis_2015, Blue_2014). Furthermore, it was identified in at-least two families with congenital heart defects where an alternate molecular basis of disease, namely segregating mutations in the TBX5 gene, causative of Holt-Oram syndrome were identified (Blue_2014, Jia_2015). Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign (2x) and once as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -

Hypertrophic cardiomyopathy 14

Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -

MYH6-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 13, 2024

The MYH6 c.4136C>T variant is predicted to result in the amino acid substitution p.Thr1379Met. This variant has been reported in two unrelated individuals with hypoplastic left heart that carried a second MYH6 variant in the compound heterozygous state (Theis et al. 2015. PubMed ID: 26085007; Theis et al. 2020. PubMed ID: 33325730). Additionally, this variant has been reported in an individual with hypoplastic left heart; however, the variant’s zygosity is unclear (Preuss et al. 2016. PubMed ID: 27760138). Additionally, this variant was found in the heterozygous state in two individuals with hypoplastic left heart syndrome (Tomita-Mitchell et al. 2016. PubMed ID: 27789736). This variant has also been reported in individuals with congenital heart defects (Table S1, Posch et al. 2011. PubMed ID: 22194935; Blue et al. 2014. PubMed ID: 25500235; Table S2, Jia et al. 2015. PubMed ID: 25931334), dilated/hypertrophic cardiomyopathy, arrhythmogenic right ventricular dysplasia (Table S2, van Lint et al. 2019. PubMed ID: 30847666; Table S1, Lopes et al. 2014. PubMed ID: 25351510; Table S4, Verdonschot et al. 2020. PubMed ID: 32880476), Brugada syndrome (Hertz et al. 2014. PubMed ID: 25467552), and mitral valve prolapse (Table S2, van Wijngaarden et al. 2020. PubMed ID: 32277046). However, in several of these cases the variant either failed to segregate with disease or another pathogenic variant was identified (Blue et al. 2014. PubMed ID: 25500235; Table S2, Jia et al. 2015. PubMed ID: 25931334). This variant is reported in 0.11% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations of pathogenicity in ClinVar ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/180425/). Although we suspect 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. -

Primary familial hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Blueprint Genetics

Dec 20, 2013

- -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Dec 01, 2017

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 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

Uncertain

0.45

BayesDel_addAF

Uncertain

0.035

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.73

D;D

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.81

T;.

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.78

D;D

MetaSVM

Uncertain

0.73

MutationAssessor

Pathogenic

3.4

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-3.7

D;D

REVEL

Pathogenic

0.81

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.034

D;D

Polyphen

1.0

D;D

Vest4

0.88

MVP

0.98

MPC

0.92

ClinPred

0.19

GERP RS

4.7

Varity_R

0.37

gMVP

0.61

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