14-23428992-A-G

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PS4PM2PM1PP3

This summary comes from the ClinGen Evidence Repository: The c.1370T>C (p.Ile457Thr) variant in MYH7 has been identified in >20 individuals with HCM (PS4_Strong; Waldmüller 2011 PMID:21750094; Fokstuen 2011 PMID:21239446; Helms 2016: 27688314; Homburger 2016 PMID:27247418; Murphy 2016 PMID:26914223; Ingles 2017 PMID:28408708; Ross 2017 PMID:28615295; Viswanathan 2017 PMID:29121657; Walsh 2017 PMID:27532257; Ko 2018 PMID:28640247; Centenary Institute Sydney pers. comm.; GeneDx pers. comm., Invitae pers. comm.; LMM pers. comm.; OGML pers. comm.). This variant also segregated with HCM in 1 affected relative (GeneDx pers. comm.); however, this data is currently insufficient to establish co-segregation with disease and apply PP1. Additionally, this variant has also been reported in 1 individual with left bundle branch block, 1 individual with sudden cardiac arrest (who carried additional variants in other cardiomyopathy associated genes) and 1 individual with myopathy who also had additional variants in myopathy-associated genes and segregated with myopathy in one affected relative (Ambry pers. comm.; CHEO pers. comm.; Invitae pers. comm.). This variant has also been identified in 0.0009% (1/113764) of European chromosomes by gnomAD v2.1.1 (PM2; http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that this variant could impact protein function (Adhikari 2019 PMID:31213605); however, this data is currently insufficient to establish functional impact and apply PS3. This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; Walsh 2017 PMID:27532257). 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 likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4; PM2; PM1; PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA010654/MONDO:0005045/002

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:13U:1

Conservation

PhyloP100: 6.07

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 Likely_pathogenic. Variant got 9 ACMG points.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM1

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4 link	c.1370T>C	p.Ile457Thr	missense_variant	Exon 14 of 40	ENST00000355349.4	NP_000248.2	P12883
MYH7	NM_001407004.1 link	c.1370T>C	p.Ile457Thr	missense_variant	Exon 13 of 39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4 link	c.1370T>C	p.Ile457Thr	missense_variant	Exon 14 of 40	1	NM_000257.4	ENSP00000347507.3		P12883

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152206

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251490

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135922

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:

0.00000410

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000450

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74356

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000835

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:13Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Pathogenic:4

Aug 03, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces isoleucine with threonine at codon 457 of the MYH7 protein. This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). 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). In vitro functional experiments have shown that this variant increases actin-activated ATPase kinetics and actin gliding velocity (PMID: 31213605). This variant has been reported in over ten individuals affected with hypertrophic cardiomyopathy (PMID: 21239446, 21750094, 26914223, 27247418, 27688314, 28615295, 28790153, 29121657, 32894683, 35026164), and in an individual affected with myosin storage myopathy with a combination of skeletal, respiratory, and cardiac muscle involvement (PMID: 31068177). This variant has been identified in 1/251490 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Aug 29, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ile457Thr variant in MYH7 has been reported in at least 10 individuals with HCM (WaldmÃ¼ller 2011, Fokstuen 2011, Murphy 2016, Walsh 2016, Viswanathan 2017, LMM data). This variant has been identified in 1/113764 European chromosomes by gnomAD (http://gnomad.broadinstitute.org/). This variant has been reported in ClinVar (Variant ID: 42840). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Of note, this variant lies in the head region of the protein and missense variants in this region are statistically more likely to be disease-associated (Walsh 2016). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PM1, PM2, PS4_Moderate, PP3. -

Dec 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 457 of the MYH7 protein (p.Ile457Thr). This variant is present in population databases (rs397516103, gnomAD 0.0009%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 21750094, 26914223, 27247418, 27532257, 27688314, 28615295, 29121657; internal data). ClinVar contains an entry for this variant (Variation ID: 42840). 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%. Experimental studies have shown that this missense change affects MYH7 function (PMID: 31213605). This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). For these reasons, this variant has been classified as Pathogenic. -

Sep 22, 2021

ClinGen Cardiomyopathy Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.1370T>C (p.Ile457Thr) variant in MYH7 has been identified in >20 individuals with HCM (PS4_Strong; Waldmüller 2011 PMID: 21750094; Fokstuen 2011 PMID: 21239446; Helms 2016: 27688314; Homburger 2016 PMID: 27247418; Murphy 2016 PMID: 26914223; Ingles 2017 PMID: 28408708; Ross 2017 PMID: 28615295; Viswanathan 2017 PMID: 29121657; Walsh 2017 PMID:27532257; Ko 2018 PMID: 28640247; Centenary Institute Sydney pers. comm.; GeneDx pers. comm., Invitae pers. comm.; LMM pers. comm.; OGML pers. comm.). This variant also segregated with HCM in 1 affected relative (GeneDx pers. comm.); however, this data is currently insufficient to establish co-segregation with disease and apply PP1. Additionally, this variant has also been reported in 1 individual with left bundle branch block, 1 individual with sudden cardiac arrest (who carried additional variants in other cardiomyopathy associated genes) and 1 individual with myopathy who also had additional variants in myopathy-associated genes and segregated with myopathy in one affected relative (Ambry pers. comm.; CHEO pers. comm.; Invitae pers. comm.). This variant has also been identified in 0.0009% (1/113764) of European chromosomes by gnomAD v2.1.1 (PM2; http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that this variant could impact protein function (Adhikari 2019 PMID: 31213605); however, this data is currently insufficient to establish functional impact and apply PS3. This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; Walsh 2017 PMID:27532257). 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 likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4; PM2; PM1; PP3. -

not provided

Pathogenic:2Uncertain:1

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYH7: PM2, PS4:Moderate, PP3, PS3:Supporting -

Oct 08, 2020

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 04, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a damaging effect with increased ATPase activity and actin gliding velocity leading to hypercontractility (PMID: 31213605); 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: 27532257, 27247418, 26914223, 21239446, 28615295, 28408708, 28790153, 29121657, 31447099, 34330286, 31068177, Morck2021[Preprint], 27688314, 32894683, 28606303, 28640247, 25125180, 30767072, 21750094, 29300372, 31213605) -

Cardiovascular phenotype

Pathogenic:2

Mar 06, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1370T>C (p.I457T) alteration is located in exon 14 (coding exon 12) of the MYH7 gene. This alteration results from a T to C substitution at nucleotide position 1370, causing the isoleucine (I) at amino acid position 457 to be replaced by a threonine (T). Based on data from gnomAD, the C allele has an overall frequency of <0.001% (1/251490) total alleles studied. The highest observed frequency was 0.001% (1/113764) of European (non-Finnish) alleles. This variant is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger, 2016; Walsh, 2017; Ambry internal data).This variant has been reported in numerous hypertrophic cardiomyopathy cohorts (Waldmüller, 2011; Fokstuen, 2011; Helms, 2016; Homburger, 2016; Ross, 2017; Viswanathan, 2017; Walsh, 2017; Ko, 2018; GeneDx pers comm; Invitae pers comm). This amino acid position is highly conserved in available vertebrate species. In one study, this variant was reported to impact protein function (Adhikari, 2019). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Jun 18, 2024

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4, PM1, PM2, PP3 -

Hypertrophic cardiomyopathy 1

Pathogenic:2

Oct 14, 2018

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1324C>T (p.Arg442Cys) variant in the MYH7 gene has been reported in multiple unrelated patients affected with hypertrophic cardiomyopathy (PMID 21239446, 21750094, 26914223, 27247418, 27532257) and is extremely rare in general population databases. This variant is located in the critical myosin head domain of MYH7 and is predicted to be damaging by multiple in silico algorithms. Therefore, this c.1324C>T (p.Arg442Cys) variant in the MYH7 gene is classified as likely pathogenic. [yunyun, 2018-10-14] -

Mar 21, 2017

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

This MYH7 Ile457Thr variant has been previously described in the literature in 9 HCM patients (Waldmuller S, et al., 2011; Fokstuen S, et al., 2011; Helms As, et al., 2016; Walsh et al., 2017). It is present in the Exome Aggregation Consortium dataset (MAF=0.000008; http://exac.broadinstitute.org/) as a singleton event. We have identified MYH7 Ile457Thr in 1 HCM proband with no established family history of disease. In silico tools and conservation scores support a deleterious role (SIFT "Deleterious"; PolyPhen-2 "Probably-damaging"; PolyPhen-HCM "Pathogenic"; MutationTaster "Disease-causing"). In a large HCM population study Walsh et al., showed that MYH7 variants identified in HCM cases were found to cluster between amino acids 181- 937 (2017), this implies that variants in this region are likely to cause a HCM phenotype. Based on this evidence, we classify MYH7 Ile457Thr as "likely pathogenic". -

Cardiomyopathy

Pathogenic:1

Jun 03, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces isoleucine with threonine at codon 457 of the MYH7 protein. This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. In vitro functional experiments have shown that this variant increases actin-activated ATPase kinetics and actin gliding velocity (PMID: 31213605). This variant has been reported in more than ten individuals affected with hypertrophic cardiomyopathy (PMID: 21239446, 21750094, 26914223, 27247418, 27688314, 28615295, 28790153, 29121657, 32894683, 35026164), and in one individual affected with myosin storage myopathy with a combination of skeletal, respiratory, and cardiac muscle involvement (PMID: 31068177). This variant has been identified in 1/251490 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

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

Nov 10, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary familial hypertrophic cardiomyopathy

Pathogenic:1

Nov 16, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MYH7 c.1370T>C (p.Ile457Thr) results in a non-conservative amino acid change located in the Myosin head, motor domain (IPR001609) 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 4e-06 in 251490 control chromosomes. c.1370T>C has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (e.g. Waldmuller_2011, Helms_2016) including in settings of multi-gene panel testing with frequent classification as likely pathogenic (e.g. Fokstuen_2011, Ingles_2017, Ross_2017, Ho_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21239446, 27688314, 30297972, 28408708, 28615295, 21750094). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as pathogenic (n=1), likely pathogenic (n=8), or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

CardioboostCm

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.95

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.85

M_CAP

Pathogenic

0.99

MetaRNN

Pathogenic

0.96

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.9

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-4.4

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0080

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.96

MutPred

0.75

Gain of catalytic residue at D461 (P = 0);

MVP

0.99

MPC

2.2

ClinPred

0.99

GERP RS

4.2

Varity_R

0.87

gMVP

1.0

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