14-23429850-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PP2PP3_StrongPP5_Very_Strong

The NM_000257.4(MYH7):c.1063G>A(p.Ala355Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:19

Conservation

PhyloP100: 4.88

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 13 ACMG points.

PP2

Missense variant in the MYH7 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 341 curated pathogenic missense variants (we use a threshold of 10). The gene has 16 curated benign missense variants. Gene score misZ: 3.9329 (above the threshold of 3.09). Trascript score misZ: 6.7889 (above the threshold of 3.09). GenCC associations: The gene is linked to hyaline body myopathy, MYH7-related skeletal myopathy, dilated cardiomyopathy 1S, congenital myopathy 7A, myosin storage, autosomal dominant, dilated cardiomyopathy, left ventricular noncompaction, myopathy, myosin storage, autosomal dominant, hypertrophic cardiomyopathy, congenital heart disease, Ebstein anomaly, arrhythmogenic right ventricular cardiomyopathy, myopathy, myosin storage, autosomal recessive, hypertrophic cardiomyopathy 1, familial isolated dilated cardiomyopathy.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

PP5

Variant 14-23429850-C-T is Pathogenic according to our data. Variant chr14-23429850-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23429850-C-T is described in Lovd as [Likely_pathogenic]. Variant chr14-23429850-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4 link	c.1063G>A	p.Ala355Thr	missense_variant	Exon 12 of 40	ENST00000355349.4	NP_000248.2	P12883
MYH7	NM_001407004.1 link	c.1063G>A	p.Ala355Thr	missense_variant	Exon 11 of 39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4 link	c.1063G>A	p.Ala355Thr	missense_variant	Exon 12 of 40	1	NM_000257.4	ENSP00000347507.3		P12883

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461790

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:19

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:7

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 02, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 22, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in multiple unrelated patients from different ethnic backgrounds with hypertrophic cardiomyopathy referred for genetic testing at GeneDx and in published literature (PMID: 20031618, 12707239, 21835320, 30022097, 31308319, 33302605, 36252119, 35838873); 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: 27247418, 21835320, 27532257, 24704860, 24793961, 18761664, 27066507, 25351510, 20031618, 23396983, 23283745, 30022097, 31308319, 33636496, 33302605, 30847666, 32894683, 12707239, 34542152, 31568572, 31722741, 30297972, 35626289, 35653365, 36252119, 29300372, 36243179, 35838873, 36264615, 37652022, 35130036) -

Jun 07, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PM1, PM2, PS4 -

Clinical Genetics, Academic Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Primary familial hypertrophic cardiomyopathy

Pathogenic:3

Jul 03, 2019

Klaassen Lab, Charite University Medicine Berlin

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Apr 18, 2017

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 19, 2020

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MYH7 c.1063G>A (p.Ala355Thr) results in a non-conservative amino acid change located in the Myosin head, motor domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251444 control chromosomes. c.1063G>A has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (e.g. Richard_2003, Ho_2018). These data indicate that the variant is very likely to be associated with disease. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Hypertrophic cardiomyopathy

Pathogenic:3

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 355 of the MYH7 protein (p.Ala355Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant hypertrophic cardiomyopathy (HCM) (PMID: 12707239, 18761664, 20031618, 21835320, 23283745, 24704860, 27247418). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42820). 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%. For these reasons, this variant has been classified as Pathogenic. -

Jan 10, 2020

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 05, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

Hypertrophic cardiomyopathy 1

Pathogenic:3

Jun 01, 2018

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

This variant has been identified as part of our research program. Refer to the 'condition' field for the phenotype of the proband(s) identified with this variant. For further information please feel free to contact us. -

Jun 12, 2024

Institute of Immunology and Genetics Kaiserslautern

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG Criteria: PS4, PM1, PM2_P, PP1, PP3, PP5; Variant was found in heterozygous state. -

Apr 12, 2023

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4, PM1, PM2, PP3, PP5 -

Cardiomyopathy

Pathogenic:1

Jun 18, 2021

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Myosin storage myopathy

Pathogenic:1

Dec 19, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Pathogenic:1

Dec 17, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A355T variant (also known as c.1063G>A), located in coding exon 10 of the MYH7 gene, results from a G to A substitution at nucleotide position 1063. The alanine at codon 355 is replaced by threonine, an amino acid with similar properties. This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This variant has been detected in several hypertrophic cardiomyopathy (HCM) cohorts in individuals reported to have HCM, and was reported to co-segregate with disease in one small family (Richard P et al. Circulation. 2003;107(17):2227-32; Kaski JP et al. Circ Cardiovasc Genet. 2009;2(5):436-41; Olivotto I et al. J Am Coll Cardiol. 2011;58(8):839-48; Zou Y et al. Mol Biol Rep. 2013;40(6):3969-76; Bos JM et al. Mayo Clin Proc. 2014;89(6):727-37; Walsh R et al. Genet Med. 2017;19(2):192-203; Mak TSH et al. Sci Rep. 2018;8(1):10846; Fernlund E et al. Genes (Basel), 2020 12;11:[Epub ahead of print]). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

CardioboostCm

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.91

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.6

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.3

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.026

Polyphen

0.96

Vest4

0.97

MutPred

0.83

Gain of catalytic residue at I356 (P = 0.0215);

MVP

0.99

MPC

2.1

ClinPred

0.98

GERP RS

3.9

Varity_R

0.73

gMVP

0.94

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