rs200939753

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PP2PP3_ModeratePP5_Strong

The NM_000257.4(MYH7):c.5329G>A(p.Ala1777Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000103 in 1,614,120 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 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:3U:12

Conservation

PhyloP100: 3.85

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.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000257.4

PP2

Missense variant where missense usually causes diseases, MYH7

PP3

MetaRNN computational evidence supports a deleterious effect, 0.9

PP5

Variant 14-23415225-C-T is Pathogenic according to our data. Variant chr14-23415225-C-T is described in ClinVar as [Uncertain_significance]. Clinvar id is 177697.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=12, Likely_pathogenic=2}. Variant chr14-23415225-C-T is described in Lovd as [Pathogenic]. Variant chr14-23415225-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4 linkuse as main transcript	c.5329G>A	p.Ala1777Thr	missense_variant	37/40	ENST00000355349.4
MYH7	NM_001407004.1 linkuse as main transcript	c.5329G>A	p.Ala1777Thr	missense_variant	36/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.5329G>A	p.Ala1777Thr	missense_variant	37/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000676

AC:

AN:

251488

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000105

AC:

154

AN:

1461892

Hom.:

Cov.:

AF XY:

0.000102

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000136

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000152

Hom.:

Bravo

AF:

0.0000642

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000778

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:3Uncertain:12

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cardiomyopathy

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 01, 2023	This missense variant replaces alanine with threonine at codon 1777 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 24793961, 27532257, 30297972), suspected hypertrophic cardiomyopathy (PMID: 33673806), dilated cardiomyopathy (PMID: 27532257), and Brugada syndrome (PMID: 25467552). Additionally, this variant has been reported in an individual affected with left ventricular noncompaction cardiomyopathy who also carried two pathogenic variants in the MYBPC3 gene (PMID: 31918855). This variant has been reported in individuals from a cohort of patients undergoing whole exome sequencing that were not selected for cardiomyopathy, arrhythmia or a family history of sudden death (PMID: 23861362, 34542152). This variant has also been identified in 21/282890 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, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Nov 30, 2021	The NM_000257.4(MYH7):c.5329G>A (p.Ala1777Thr) variant has been identified in at least 14 individuals with HCM, 2 of whom had an additional variant in another gene that may contribute to their disease, 1 individual with RCM with another pathogenic MYH7 variant, and 5 individuals with DCM including 2 that also had disease-causing variants (Richard 2003 PMID:12707239; Bos 2014 PMID:24793961; Homburger 2016 PMID:27247418; Walsh 2017 PMID: 27532257; Ho 2018 PMID:30297972; Ambry pers. comm.; GeneDx pers. comm.; LMM pers. comm.; OMGL pers. comm). This variant has also been identified in 1 individual with LVNC requiring transplant who also had 2 pathogenic MYBPC3 variants, 1 individual with Brugada syndrome, and 2 individuals with myopathy - 1 with myofibrillar myopathy and 1 with distal and axial myopathy (Hertz 2014 PMID:25467552; Evilä 2016 PMID:26627873; Chanson 2016 PMID:26969127; Liu 2020 PMID:31918855). This variant has been observed to segregate with DCM in 1 relative of a proband with DCM as well as not segregate with HCM in an affected sibling of a proband with HCM (OMGL per. comm.). Because of the variability in phenotypes observed in individuals with this variant and because PS4 is only applicable when the variant is absent or rare in large population studies, the PS4 criterion was not applied (Kelly 2018 PMID:29300372). Additionally, the segregation data is currently insufficient to establish segregation or non-segregation with disease and therefore neither PP1 nor BS4 were applied. This variant has been identified in 0.008% (FAF 95% CI; 17/129,190) of European chromosomes in gnomAD v.2.1.1 (http://gnomad.broadinstitute.org) and is above the threshold of 0.004%, therefore PM2 cannot be applied. Computational prediction tools and conservation do not provide evidence for or against an impact to the protein. In summary, due to conflicting evidence, this variant is classified as uncertain significance for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): None. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 07, 2023	This missense variant replaces alanine with threonine at codon 1777 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 24793961, 27532257, 30297972), suspected hypertrophic cardiomyopathy (PMID: 33673806), dilated cardiomyopathy (PMID: 27532257), and Brugada syndrome (PMID: 25467552). Additionally, this variant has been reported in an individual affected with left ventricular noncompaction cardiomyopathy who also carried two pathogenic variants in the MYBPC3 gene (PMID: 31918855). This variant has been reported in individuals from a cohort of patients undergoing whole exome sequencing that were not selected for cardiomyopathy, arrhythmia or a family history of sudden death (PMID: 23861362, 34542152). This variant has also been identified in 21/282890 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. -

Primary familial hypertrophic cardiomyopathy

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Apr 24, 2015	- -
Likely pathogenic, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 08, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 10, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27247418, 25467552, 23447461, 25961035, 26969127, 26627873, 27532257, 31918855, 36095024, 23861362, 33673806, 29300372, 24793961, 32894683, 34542152, 12707239) -

Hypertrophic cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 05, 2019	The p.Ala1777Thr variant in MYH7 has been reported in 6 individuals with HCM, 1 individual with DCM, 1 individual with myopathy, and 1 individual with RCM who carried a second pathogenic MYH7 variant (Richard 2003, Ng 2013, Walsh 2017, Evila 2016, Bos 2014, Hertz 2014, LMM data). The p.Ala1777Thr variant has also been identified in 17/126714 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200939753). Clinvar: Path (University Hosp of Strasbourg), LP (Blueprint, ClinSeq), VUS (GeneDx, Invitae, Ambry, MYH7 expert panel). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. Furthermore, in vitro functional studies suggest that the variant may not impact protein function (Wallefeld 2010); however, these types of assays may not accurately represent biological function. In summary, given the broad phenotypic spectrum associated with this variant and the presence of conflicting data, the clinical significance of the p.Ala1777Thr variant is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1777 of the MYH7 protein (p.Ala1777Thr). This variant is present in population databases (rs200939753, gnomAD 0.01%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 12707239, 24793961, 27247418, 27532257, 32894683, 33673806; Invitae). ClinVar contains an entry for this variant (Variation ID: 177697). 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. -

Hypertrophic cardiomyopathy 1

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Feb 01, 2022	- -

Idiopathic camptocormia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Department of Neurology, University Hospital of Strasbourg

Jan 01, 2014

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Nov 03, 2023

Variant summary: MYH7 c.5329G>A (p.Ala1777Thr) results in a non-conservative amino acid change located in the Myosin tail domain (IPR002928) 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 251488 control chromosomes, predominantly at a frequency of 0.00012 within the Non-Finnish European subpopulation in the gnomAD database. 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.5329G>A has been reported in the literature in individuals affected with Cardiomyopathy. These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. 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: 12707239, 23861362, 24793961, 27247418, 27532257, 25467552, 29300372, 33673806). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=10) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Jul 19, 2021

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 21, 2022

The p.A1777T variant (also known as c.5329G>A), located in coding exon 35 of the MYH7 gene, results from a G to A substitution at nucleotide position 5329. The alanine at codon 1777 is replaced by threonine, an amino acid with similar properties. This variant has been reported in individuals with hypertrophic cardiomyopathy (HCM) (Richard P et al. Circulation. 2003;107(17):2227-32); Bos JM et al. Mayo Clin. Proc., 2014 Jun;89:727-37; 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 alteration was also identified in a patient reported to have distal and axial myopathy, a patient reported to have myofibrillar myopathy (Evilä A et al. Neuromuscul Disord. 2016;26(1):7-15; Chanson JB et al. Eur J Neurol. 2016; 23(6):1086-92). This variant has been detacted in a case with Brugada syndrome and co-occurred with MYBPC3 variants in an individual with noncompaction cardiomyopathy (Hertz CL et al. Int. J. Legal Med., 2015 Jul;129:793-800; Liu S et al. Int J Cardiol. 2020 03;302:117-123). This variant has also been detected in individuals from a cohort not indicated as having cardiomyopathy or skeletal myopathy; however details were limited (Park J et al. Hum Mol Genet. 2022 03;31(5):827-837). This alteration has been reported as a secondary cardiac variant in an exome cohort (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

CardioboostCm

Benign

0.064

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Pathogenic

0.22

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Pathogenic

0.80

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.89

M_CAP

Pathogenic

0.86

MetaRNN

Pathogenic

0.90

MetaSVM

Uncertain

0.46

MutationAssessor

Uncertain

2.7

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-2.3

REVEL

Pathogenic

0.69

Sift

Uncertain

0.028

Sift4G

Benign

0.19

Polyphen

0.98

Vest4

0.81

MutPred

0.42

Gain of phosphorylation at A1777 (P = 0.0699);

MVP

0.94

MPC

1.3

ClinPred

0.39

GERP RS

5.1

Varity_R

0.28

gMVP

0.86

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