rs750987717

chr14-23416240-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP2 PP3_Moderate

The NM_000257.4(MYH7):c.4717G>A(p.Glu1573Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000539 in 1,613,820 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 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000059 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:13
• Conservation: PhyloP100: 5.73

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]

MHRT (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MYH7
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.909

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4	c.4717G>A	p.Glu1573Lys	missense_variant	34/40	ENST00000355349.4
MHRT	NR_126491.1	n.501C>T		non_coding_transcript_exon_variant	3/6
MYH7	NM_001407004.1	c.4717G>A	p.Glu1573Lys	missense_variant	33/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4	c.4717G>A	p.Glu1573Lys	missense_variant	34/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152006 Hom.: 0 Cov.: 32

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000597 AC: 15 AN: 251370 Hom.: 0 AF XY: 0.0000810 AC XY: 11 AN XY: 135850

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: 0.0000654

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.0000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000588 AC: 86 AN: 1461814 Hom.: 0 Cov.: 34 AF XY: 0.0000646 AC XY: 47 AN XY: 727190

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: 0.0000116

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.0000701

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152006 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74242

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: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000697 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:5

Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2018	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 05, 2023	Identified in an individual affected with cardiac defects and in an unaffected relative, as well as in an individual with left ventricular noncompation in the published literature (Postma et al., 2011; Miszalski-Jamka et al., 2017); Reported in a patient with HCM referred for genetic testing at GeneDx who harbored an additional pathogenic variant that may explain their phenotype; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 222729; ClinVar); This variant is associated with the following publications: (PMID: 21127202, 32880476, 28798025, 34542152, Vepslinen2022[CaseReport]) -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 17, 2022	Variant summary: MYH7 c.4717G>A (p.Glu1573Lys) results in a conservative amino acid change in the encoded protein sequence within the Myosin tail (IPR002928). Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251370 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MYH7 causing Cardiomyopathy (6e-05 vs 0.0013), allowing no conclusion about variant significance. c.4717G>A has been reported in the literature in individuals affected with Cardiomyopathy, Left ventricular hypertrabeculation, and Ebstein's anomaly (Jamka_2017, Verdonschot_2020, Postma_2011, Haas_2015). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Co-occurrences with another pathogenic variant has been reported (MYH7 c.2167C>T, p.Arg723Gly, internal data), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 26, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 proband with ebstein anomaly and mild hypertrabeculation of the apex, but also identified in her father with normal echo; ClinVar: VUS for first degree atrioventricular block -

Cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 02, 2023	This missense variant replaces glutamic acid with lysine at codon 1573 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 an individual affected with left ventricular non-compaction (PMID: 28798025) and in an individual with dilated cardiomyopathy (PMID: 32880476). This variant has also been reported in an individual affected with Ebstein anomaly and perimembranous ventricular septal defect, as well as in the unaffected father (PMID: 21127202). This variant has been identified in 15/251370 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 09, 2022	This missense variant replaces glutamic acid with lysine at codon 1573 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 an individual affected with left ventricular non-compaction (PMID: 28798025) and in an individual with dilated cardiomyopathy (PMID: 32880476). This variant has also been reported in an individual affected with Ebstein anomaly and perimembranous ventricular septal defect, as well as in the unaffected father (PMID: 21127202). This variant has been identified in 15/251370 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. -

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 14, 2023

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. 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. ClinVar contains an entry for this variant (Variation ID: 222729). This missense change has been observed in individual(s) with MYH7-related conditions (PMID: 21127202, 28798025, 32880476). This variant is present in population databases (rs750987717, gnomAD 0.01%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1573 of the MYH7 protein (p.Glu1573Lys). -

MYH7-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 30, 2023

The MYH7 c.4717G>A variant is predicted to result in the amino acid substitution p.Glu1573Lys. This variant was reported in individuals with Ebstein anomaly, left ventricular noncompaction, or dilated cardiomyopathy (Postma et al. 2011. PubMed ID: 21127202; Table S6, Haas et al. 2014. PubMed ID: 25163546; Table S3, Miszalski-Jamka et al. 2017. PubMed ID: 28798025; Table S4, Verdonschot et al. 2020. PubMed ID: 32880476). However, this variant was also documented in unaffected family members or control individuals (Postma et al. 2011. PubMed ID: 21127202; Table S6, Park et al. 2022. PubMed ID: 34542152). This variant is reported in 0.014% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-23885449-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2022

The p.E1573K variant (also known as c.4717G>A), located in coding exon 32 of the MYH7 gene, results from a G to A substitution at nucleotide position 4717. The glutamic acid at codon 1573 is replaced by lysine, an amino acid with similar properties. This variant was detected in a proband with Ebstein's anomaly, mild apical hypertrabeculation and VSD, but was also detected in an unaffected parent (Postma AV et al. Circ Cardiovasc Genet, 2011 Feb;4:43-50). This variant has also been detected in a case reported to have left ventricular non-compaction, a case with dilated cardiomyopathy, and in a hypertrophic cardiomyopathy cohort; however, details were limited and additional variants in cardiac-related genes were also detected in some cases (Miszalski-Jamka K et al. Circ Cardiovasc Genet, 2017 Aug;10; Verdonschot JAJ et al. Circ Genom Precis Med, 2020 Oct;13:476-487; Harper AR et al. Nat Genet, 2021 Feb;53:135-142). This variant has also been detected in three individuals from an exome sequencing cohort who were not known to have cardiomyopathy or skeletal myopathy (Park J et al. Hum Mol Genet, 2022 Mar;31:827-837). This amino acid position is well 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. -

First degree atrioventricular block Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Blueprint Genetics

Aug 27, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
CardioboostCm	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Pathogenic	0.19
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Pathogenic	3.6	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-2.5	D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.85	P
Vest4		0.87
MVP		0.91
MPC		1.5
ClinPred		0.71	D
GERP RS		4.5
Varity_R		0.61
gMVP		0.76

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

Other links and lift over

dbSNP: rs750987717; hg19: chr14-23885449; COSMIC: COSV62522323; COSMIC: COSV62522323;