14-23417646-C-T

Position:

chr14-23417646-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

This summary comes from the ClinGen Evidence Repository: The c.4210G>A (p.Val1404Met) variant in MYH7 has been identified in 3 individuals with HCM (Wang 2014 PMID:25132132; Invitae pers. comm.) and also segregated in 1 affected relative with HCM (Invitae pers. comm.); however this data is currently insufficient to apply PP1. Of note, 1 of the 2 affected individuals from Invitae also carried a splice variant in MYBPC3 and was in their mid 20s at the time of testing. This variant was identified in 0.004% (FAF 95% CI; 9/129152) of European chromosomes by gnomAD v2.1.1 (http://gnomad.broadinstitute.org). Since the MYH7 specifications state that PS4 is only applicable if the variant is absent or rare in large population studies, the PS4 criterion was not applied (Kelly 2018 PMID:29300372). Computational prediction tools and conservation analysis were mixed about the potential impact of this variant. In summary, due to insufficient evidence, this variant meets criteria to be classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): none. LINK:https://erepo.genome.network/evrepo/ui/classification/CA014652/MONDO:0005045/002

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000063 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:15

Conservation

PhyloP100: 2.60

Variant links:

Genes affected

MYH7 (HGNC:7577): (myosin heavy chain 7) Muscle myosin is a hexameric protein containing 2 heavy chain subunits, 2 alkali light chain subunits, and 2 regulatory light chain subunits. This gene encodes the beta (or slow) heavy chain subunit of cardiac myosin. It is expressed predominantly in normal human ventricle. It is also expressed in skeletal muscle tissues rich in slow-twitch type I muscle fibers. Changes in the relative abundance of this protein and the alpha (or fast) heavy subunit of cardiac myosin correlate with the contractile velocity of cardiac muscle. Its expression is also altered during thyroid hormone depletion and hemodynamic overloading. Mutations in this gene are associated with familial hypertrophic cardiomyopathy, myosin storage myopathy, dilated cardiomyopathy, and Laing distal myopathy. [provided by RefSeq, May 2022]

MYH7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH7	NM_000257.4 link	c.4210G>A	p.Val1404Met	missense_variant	31/40	ENST00000355349.4	NP_000248.2	P12883
MYH7	NM_001407004.1 link	c.4210G>A	p.Val1404Met	missense_variant	30/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4 link	c.4210G>A	p.Val1404Met	missense_variant	31/40	1	NM_000257.4	ENSP00000347507.3		P12883

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000278

AC:

AN:

251426

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000630

AC:

AN:

1460698

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

726660

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000162

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000656

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000115

Hom.:

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:15

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:5

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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 24, 2023	Reported in association with HCM and DCM in published literature (Wang et al., 2014; van Lint et al., 2019; Verdonschot et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24215330, 34542152, 35653365, 30847666, 32880476, 25132132) -
Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jun 29, 2021	- -

Cardiomyopathy

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 29, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 10, 2024	This missense variant replaces valine with methionine at codon 1404 of the MYH7 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with hypertrophic cardiomyopathy (PMID: 25132132, 30847666); one of these individuals also carried an additional likely pathogenic variant in the same gene (PMID: 30847666). This variant has also been reported in two individuals affected with dilated cardiomyopathy (PMID: 32880476, 37904629). This variant has been identified in 10/282824 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 23, 2023	This missense variant replaces valine with methionine at codon 1404 of the MYH7 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 25132132) and in an individual affected with dilated cardiomyopathy (PMID: 32880476). This variant has been identified in 10/282824 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hypertrophic cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2025	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1404 of the MYH7 protein (p.Val1404Met). This variant is present in population databases (rs371552806, gnomAD 0.006%). This missense change has been observed in individual(s) with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 25132132, 32880476). ClinVar contains an entry for this variant (Variation ID: 42999). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. 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. -
Uncertain significance, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Jun 16, 2021	The c.4210G>A (p.Val1404Met) variant in MYH7 has been identified in 3 individuals with HCM (Wang 2014 PMID:25132132; Invitae pers. comm.) and also segregated in 1 affected relative with HCM (Invitae pers. comm.); however this data is currently insufficient to apply PP1. Of note, 1 of the 2 affected individuals from Invitae also carried a splice variant in MYBPC3 and was in their mid 20s at the time of testing. This variant was identified in 0.004% (FAF 95% CI; 9/129152) of European chromosomes by gnomAD v2.1.1 (http://gnomad.broadinstitute.org). Since the MYH7 specifications state that PS4 is only applicable if the variant is absent or rare in large population studies, the PS4 criterion was not applied (Kelly 2018 PMID:29300372). Computational prediction tools and conservation analysis were mixed about the potential impact of this variant. In summary, due to insufficient evidence, this variant meets criteria to be classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): none. -

Hypertrophic cardiomyopathy 1

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jul 21, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	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, missense variants have been proposed to act in a dominant negative manner (PMID: 24714796). (I) 0108 - This gene is associated with both recessive and dominant disease. Disease associated with this gene usually has autosomal dominant inheritance; however, a recessive inheritance pattern has been observed in severe cases (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 29300372). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (10 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated myosin tail 1 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 classified as a VUS by an expert panel, and has been observed and classified as a VUS in multiple individuals with DCM and HCM (ClinVar, PMID: 29687901, 27247418, 30847666, 25132132, 24215330, 32880476). (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) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Dilated cardiomyopathy 1S

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

The observed missense c.4210G>A(p.Val1404Met) variant in MYH7 gene has been reported previously in individuals affected with cardiomyopathy (Verdonschot JAJ, et al., 2020; Wang J, et al., 2014). The p.Val1404Met variant has been reported with allele frequency of 0.003% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Uncertain Significance (multiple submissions). The amino acid change p.Val1404Met in MYH7 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Val at position 1404 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. However, additional functional studies will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS). -

Primary dilated cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 05, 2019

The p.Val1404Met variant in MYH7 has been reported in 1 individual with HCM (Wang 2014), and one with an unspecified mitochondrial disorder, but was also seen in this individual's unaffected father (DaRe 2013). In addition, it has been identified by our laboratory in 1 Caucasian individual with DCM. This variant has been identified in 2/66696 MYH7 chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs371552806). Clinvar: VUS (GeneDx, Invitae). Computational prediction tools and conservation analysis suggest that the p.Val1404Met variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Val1404Met variant is uncertain. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2021

The c.4210G>A (p.V1404M) alteration is located in exon 31 (coding exon 29) of the MYH7 gene. This alteration results from a G to A substitution at nucleotide position 4210, causing the valine (V) at amino acid position 1404 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

CardioboostCm

Uncertain

0.75

BayesDel_addAF

Benign

-0.078

BayesDel_noAF

Benign

-0.19

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.92

MetaSVM

Uncertain

0.25

MutationAssessor

Benign

2.0

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-1.7

REVEL

Pathogenic

0.81

Sift

Benign

0.13

Sift4G

Benign

0.21

Polyphen

1.0

Vest4

0.65

MVP

0.93

MPC

1.4

ClinPred

0.63

GERP RS

5.0

Varity_R

0.27

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

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