rs397516201

Positions:

chr14-23418249-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS4PM2PP3PP1_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000257.4(MYH7):c.4130C>T (p.Thr1377Met) variant in MYH7 has been reported in >30 individuals with HCM (PS4; Richard 2003 PMID:12707239; Van Driest 2004 PMID:15358028; Girolami 2006 PMID:16858239; Millat 2010 PMID:20624503; Witjas-Paalberends 2013 PMID:23674513; Berge 2014 PMID:24111713; Helms 2014 PMID:25031304; Adler 2016 PMID:26743238; Montag 2017 PMID:29101517; Pérez-Sánchez 2018 PMID:28687478; Wang 2018 PMID:29343710; Ambry pers. comm.; CHEO pers. comm.; GeneDx pers. comm., Invitae pers. comm.; LMM pers. comm.; Mayo pers. comm.; OMGL pers. comm.). This variant segregated with disease in >10 affected relatives with HCM in at least 4 families (PP1_strong; Pérez-Sánchez 2018 PMID:28687478; Wang 2018 PMID:29343710; LMM pers. comm.). This variant was identified in 0.0009% (1/113754) of European chromosomes by gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PP1_Strong; PM2; PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA014494/MONDO:0005045/002

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:18

Conservation

PhyloP100: 9.64

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 Pathogenic. Variant got 11 ACMG points.

PS4

PM2

PP1

PP3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4 linkuse as main transcript	c.4130C>T	p.Thr1377Met	missense_variant	30/40	ENST00000355349.4
MYH7	NM_001407004.1 linkuse as main transcript	c.4130C>T	p.Thr1377Met	missense_variant	29/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.4130C>T	p.Thr1377Met	missense_variant	30/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152212

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:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251476

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135920

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461260

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726936

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74368

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:

0.0000941

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	MYH7: PP1:Moderate, PS4:Moderate, PP2, PP3 -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 03, 2024	Classified as pathogenic by the ClinGen Cardiomyopathy Variant Curation Expert (Clinvar; Variation ID: 42992); Not observed at significant frequency in large population cohorts (gnomAD); 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: 16352453, 15358028, 20800588, 25031304, 18409188, 20624503, 21239446, 24835277, 18533079, 23674513, 12707239, 24111713, 24510615, 16858239, 28971120, 27247418, 27532257, 28202948, 29988065, 28687478, 29101517, 29300372, 26743238, 27688314, 30165862, 30665703, 30972196, 29169752, 24093860, 32344918, 30297972, 33673806, 33407484, 32894683, 33658040, 35626289, 35653365, 35208637, 32492895, 29343710) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 08, 2018	PP1_strong, PP2, PP3, PM2_supporting, PS4 -

Hypertrophic cardiomyopathy

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 07, 2022	The p.Thr1377Met variant in MYH7 has been reported in > 35 individuals with HCM (Richard 2003 PMID: 12707239, Van Driest 2004 PMID: 15358028, Girolami 2006 PMID: 16858239, Fokstuen 2008 PMID: 18409188, Olivotto 2008 PMID: 18533079, Millat 2010 PMID: 20624503, Foksteun 2011 PMID: 21239446, Witjas-Paalberends 2013 PMID: 223674513, Adler 2014 PMID: 26743238, Berge 2014 PMID: 24111713, Helms 2014 PMID: 25031304, Kapplinger 2014 PMID: 24510615, Walsh 2016 PMID: 27532257, Song 2017 PMID: 28202948, Perez-Sanchez 2018 PMID: 28687478, Wang 2018 PMID: 29343710, LMM data). This variant has also been shown to segregate in >10 relatives from 7 families, (Perez-Sanchez 2018 PMID: 28687478, Wang 2018 PMID: 29343710, LMM data). It has also been identified in 0.0009% (1/113754) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Thr1377Met variant may impact the protein. Moreover, this variant was classified as Pathogenic on February 25, 2019 by the ClinGen-approved Cardiomyopathy Variant Curation expert panel (Variation ID 42992). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM2_supporting, PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 06, 2023	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1377 of the MYH7 protein (p.Thr1377Met). This variant is present in population databases (rs397516201, gnomAD 0.0009%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12707239, 16858239, 18409188, 20800588, 24111713, 25031304, 27247418, 27532257, 32344918). ClinVar contains an entry for this variant (Variation ID: 42992). 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 MYH7 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Nov 23, 2021	The NM_000257.4(MYH7):c.4130C>T (p.Thr1377Met) variant in MYH7 has been reported in >30 individuals with HCM (PS4; Richard 2003 PMID: 12707239; Van Driest 2004 PMID: 15358028; Girolami 2006 PMID: 16858239; Millat 2010 PMID: 20624503; Witjas-Paalberends 2013 PMID: 23674513; Berge 2014 PMID: 24111713; Helms 2014 PMID: 25031304; Adler 2016 PMID: 26743238; Montag 2017 PMID: 29101517; Pérez-Sánchez 2018 PMID: 28687478; Wang 2018 PMID: 29343710; Ambry pers. comm.; CHEO pers. comm.; GeneDx pers. comm., Invitae pers. comm.; LMM pers. comm.; Mayo pers. comm.; OMGL pers. comm.). This variant segregated with disease in >10 affected relatives with HCM in at least 4 families (PP1_strong; Pérez-Sánchez 2018 PMID: 28687478; Wang 2018 PMID: 29343710; LMM pers. comm.). This variant was identified in 0.0009% (1/113754) of European chromosomes by gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PP1_Strong; PM2; PP3. -

Cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jun 15, 2023

- -

Congenital myopathy with fiber type disproportion;C1834481:Dilated cardiomyopathy 1S;C1842160:Myosin storage myopathy;C1850709:Myopathy, myosin storage, autosomal recessive;C3495498:Hypertrophic cardiomyopathy 1;C4552004:MYH7-related skeletal myopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 19, 2022

- -

Primary familial hypertrophic cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

May 21, 2015

- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 08, 2021

The p.T1377M pathogenic mutation (also known as c.4130C>T), located in coding exon 28 of the MYH7 gene, results from a C to T substitution at nucleotide position 4130. The threonine at codon 1377 is replaced by methionine, an amino acid with similar properties. This variant has been previously detected in numerous hypertrophic cardiomyopathy cohorts (Richard P et al. Circulation. 2003;107(17):2227-32 (reported as c.19222C>T); Van Driest SL et al. J Am Coll Cardiol. 2004;44(3):602-10; Olivotto I et al. Mayo Clin Proc. 2008;83(6):630-8; Millat G et al. Eur J Med Genet. 2010;53:261-7; Fokstuen S et al. J. Med. Genet. 2011;48:572-6; Berge KE et al. Clin Genet. 2014;86(4):355-60; Walsh R et al. Genet. Med. 2017;19:192-203). In addition, this alteration has been shown to segregate with disease in a large Chinese family and has been reported to segregate with disease in several other families (Pérez-Sánchez I et al. Rev Esp Cardiol (Engl Ed), 2018;71:146-154; Wang J et al. Sci Rep, 2018;8:973). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

MYH7-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Dec 10, 2023

- -

Hypertrophic cardiomyopathy 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3billion

Jan 03, 2022

The variant was co-segregated with Cardiomyopathy, hypertrophic, 1 in multiple affected family members with additional meioses meeting strong evidence levels (PMID: 12707239, 27247418, 25031304, 20800588, 18409188, 16858239, 24111713, 27532257) (PP1_S). The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 25031304, 18533079, 23674513, 27532257, 21239446, 20624503, 16858239, 12707239, 30297972, 24093860, PS4_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.862, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2_M).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

CardioboostCm

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.84

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.81

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.94

MetaSVM

Uncertain

0.73

MutationAssessor

Pathogenic

4.0

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-3.7

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.030

Polyphen

1.0

Vest4

0.93

MutPred

0.55

Loss of phosphorylation at T1377 (P = 0.0419);

MVP

0.99

MPC

1.6

ClinPred

0.99

GERP RS

4.8

Varity_R

0.43

gMVP

0.87

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