chr14-23415267-C-T

Position:

chr14-23415267-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PP2PP3_Strong

The NM_000257.4(MYH7):c.5287G>A(p.Ala1763Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000112 in 1,614,260 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:21

Conservation

PhyloP100: 7.04

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 7 ACMG points.

PM1

In a helix (size 38) in uniprot entity MYH7_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_000257.4

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYH7. . Gene score misZ 3.9329 (greater than the threshold 3.09). Trascript score misZ 6.7889 (greater than threshold 3.09). GenCC has associacion of gene with 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, 0.945

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH7	NM_000257.4 linkuse as main transcript	c.5287G>A	p.Ala1763Thr	missense_variant	37/40	ENST00000355349.4	NP_000248.2	P12883
MYH7	NM_001407004.1 linkuse as main transcript	c.5287G>A	p.Ala1763Thr	missense_variant	36/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.5287G>A	p.Ala1763Thr	missense_variant	37/40	1	NM_000257.4	ENSP00000347507.3		P12883

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000676

AC:

AN:

251494

Hom.:

AF XY:

0.0000662

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000112

AC:

164

AN:

1461894

Hom.:

Cov.:

AF XY:

0.000102

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000129

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000112

AC:

AN:

152366

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74516

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000225

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:21

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Uncertain:5

Uncertain significance, criteria provided, single submitter	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Nov 27, 2018	The Ala1763Thr variant has been previously reported in 4 SUD cases (Dewar LJ et al., 2017), 3 DCM cases (Broch K, et al., 2018; LMM, Pers. Comm.; Phosphorus inc, ClinVar SCV000679791), 1 LVNC case (Blueprint, ClinVar SCV000264098), 3 myopathy cases (Phosphorus inc, ClinVar SCV000679793-5) and 7 HCM cases (Walsh et al., 2017; Cecconi M, et al., 2016; Bos JM, et al., 2014; Berge & Leren, 2014; Invitae, ClinVar SCV000546187; Phosphorus inc, ClinVar SCV000679792). It is present at an elevated frequency of 0.0000685 in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). The MYH7 Ala1736Thr variant occurs in a conserved region, and in silico tools (SIFT, PolyPhen2, MutationTaster and CADD) support a damaging role for this variant. We have identified this variant in a single HCM proband who has no family history of disease (Ingles J et al., 2017; Burns C, et al., 2017). Based on the adapted ACMG guidelines (Kelly MA, et al., 2018), this variant is not rare in the general population and therefore probands cannot be counted as evidence. In silico tools predict it to deleterious (PP3), therefore we classify MYH7 Ala1763Thr as a variant of 'uncertain significance'. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 30, 2022	The p.Ala1763Thr variant in MYH7 has been reported in 1 infant with HCM, who also carried a pathogenic variant in MYBC3, and 6 individuals with cardiomyopathy (5 with HCM, and 1 with DCM: Berge 2014, Bos 2014, Alfares 2015, Walsh 2017, LMM data). One of the individuals with HCM carried an additional pathogenic variant in MYH7 sufficient to explain their disease. This variant has also been identified in 14/126724 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs727504355). This variant was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Ala1763Thr variant is uncertain. ACMG/AMP criteria applied: BS1_P. -
Uncertain significance, criteria provided, single submitter	research	Genetics and Genomics Program, Sidra Medicine	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1763 of the MYH7 protein (p.Ala1763Thr). This variant is present in population databases (rs727504355, gnomAD 0.01%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy, dilated cardiomyopathy or sudden death (PMID: 24111713, 24793961, 25611685, 26468400, 27532257, 27600940, 28790153, 28807990). ClinVar contains an entry for this variant (Variation ID: 177846). 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%. 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, criteria provided, single submitter	clinical testing	Center for Human Genetics, University of Leuven	Oct 31, 2018	- -

Cardiomyopathy

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jun 06, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 17, 2024	This missense variant replaces alanine with threonine at codon 1763 of the MYH7 protein. Computational prediction suggests that this variant may have 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 multiple individuals affected with hypertrophic cardiomyopathy (PMID: 24111713, 24793961, 25611685, 27532257, 27600940, 28790153), in one individual affected with dilated cardiomyopathy (PMID: 26468400), and in an individual affected with sudden unexplained death (PMID: 28807990). One individual affected with hypertrophic cardiomyopathy carried a pathogenic variant in a different gene in addition to this variant (PMID: 27600940). This variant has been identified in 21/282898 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	Dec 06, 2023	This missense variant replaces alanine with threonine at codon 1763 of the MYH7 protein. Computational prediction tool indicates that this variant may have 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 multiple individuals affected with hypertrophic cardiomyopathy (PMID: 31513939, 24111713, 24793961, 25611685, 27532257, 27600940, 28790153), in one individual affected with dilated cardiomyopathy (PMID: 26468400), and in an individual affected with sudden unexplained death (PMID: 28807990). One individual affected with hypertrophic cardiomyopathy carried a pathogenic variant in a different gene in addition to this variant (PMID: 27600940). This variant has been identified in 21/282898 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. -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 05, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	MYH7: PM2, PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 21, 2019	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Feb 20, 2023

Variant summary: MYH7 c.5287G>A (p.Ala1763Thr) results in a non-conservative amino acid change located in the Myosin tail domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251494 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MYH7 causing Cardiomyopathy (6.8e-05 vs 0.0013), allowing no conclusion about variant significance. c.5287G>A has been reported in the literature in individuals affected with HCM, DCM, or sudden unexpected death. These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Co-occurrences with a pathogenic variant has been reported (TTN c.48868C>T, p.Arg16290X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten 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 uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Dilated cardiomyopathy 1S

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Phosphorus, Inc.

Aug 01, 2017

- -

Myosin storage myopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Phosphorus, Inc.

Aug 01, 2017

- -

MYH7-related skeletal myopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Phosphorus, Inc.

Aug 01, 2017

- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 18, 2022

- -

Myopathy, myosin storage, autosomal recessive

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Phosphorus, Inc.

Aug 01, 2017

- -

Left ventricular noncompaction cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Blueprint Genetics

Dec 16, 2014

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 09, 2023

The p.A1763T variant (also known as c.5287G>A), located in coding exon 35 of the MYH7 gene, results from a G to A substitution at nucleotide position 5287. The alanine at codon 1763 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in individuals with hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and sudden death; however, clinical details were limited (Bos JM et al. Mayo Clin. Proc., 2014 Jun;89:727-37; Berge KE et al. Clin. Genet., 2014 Oct;86:355-60; Broch K et al. Open Heart, 2015 Oct;2:e000271; Alfares AA et al. Genet. Med., 2015 Nov;17:880-8; Dewar LJ et al. Circ Cardiovasc Genet. 2017 Aug;10(4); Ramchand J et al. J Am Heart Assoc. 2020 01;9(2):e013346). In one HCM case, the individual also had a second alteration in another cardiac-related gene (Cecconi M et al. Int. J. Mol. Med., 2016 Oct;38:1111-24). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

MYH7-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 03, 2024

The MYH7 c.5287G>A variant is predicted to result in the amino acid substitution p.Ala1763Thr. This variant was reported in multiple individuals with hypertrophic cardiomyopathy or dilated cardiomyopathy (Berge et al. 2014. PubMed ID: 24111713; Broch et al. 2015. PubMed ID: 26468400; Table S1B, Walsh et al. 2017. PubMed ID: 27532257; Table S2, Burns et al. 2017. PubMed ID: 28790153; Table S2, Robyns et al. 2020. PubMed ID: 31513939), as well as in four pediatric cases of sudden unexplained death (Dewar et al. 2017. PubMed ID: 28807990). However, another cohort study found this variant only in eight individuals in the control group and none of the hypertrophic cardiomyopathy patients (Table S6, Park et al. 2022. PubMed ID: 34542152). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/177846/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hypertrophic cardiomyopathy 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Phosphorus, Inc.

Aug 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

CardioboostCm

Pathogenic

0.93

BayesDel_addAF

Uncertain

0.033

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.83

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.86

M_CAP

Pathogenic

0.83

MetaRNN

Pathogenic

0.94

MetaSVM

Uncertain

0.37

MutationAssessor

Pathogenic

3.0

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-2.6

REVEL

Pathogenic

0.85

Sift

Uncertain

0.011

Sift4G

Benign

0.12

Polyphen

0.99

Vest4

0.92

MVP

0.97

MPC

1.5

ClinPred

0.82

GERP RS

5.3

Varity_R

0.35

gMVP

0.92

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