rs187073962

chr14-23413845-C-Gchr14-23413845-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 3P and 10B. PM1 PP2 BP4_Moderate BP6_Very_Strong

The NM_000257.4(MYH7):c.5704G>C(p.Glu1902Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000353 in 1,614,266 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1902K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Likely benign reviewed by expert panel U:5 B:10
• Conservation: PhyloP100: 6.05

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]

ACMG classification

Verdict is Benign. Variant got -7 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, 8 uncertain in NM_000257.4
• PP2: Missense variant where missense usually causes diseases, MYH7
• BP4: Computational evidence support a benign effect (MetaRNN=0.14829487).
• BP6: Variant 14-23413845-C-G is Benign according to our data. Variant chr14-23413845-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 43082.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr14-23413845-C-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4	c.5704G>C	p.Glu1902Gln	missense_variant	39/40	ENST00000355349.4
MYH7	NM_001407004.1	c.5704G>C	p.Glu1902Gln	missense_variant	38/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4	c.5704G>C	p.Glu1902Gln	missense_variant	39/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152254 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000103 AC: 26 AN: 251484 Hom.: 0 AF XY: 0.0000956 AC XY: 13 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00141

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000356 AC: 52 AN: 1461894 Hom.: 0 Cov.: 32 AF XY: 0.0000316 AC XY: 23 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00121

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152372 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74512

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000770

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000491

ExAC AF: 0.0000741 AC: 9

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:5 Benign:10

Revision: reviewed by expert panel

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 05, 2016	proposed classification - variant undergoing re-assessment, contact laboratory -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	-	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Glu1902Gln (p.E1902Q; c.5704G>C) in MYH7. This variant is novel. This variant results in glutamate at codon 1902 replaced by glutamine, an amino acid with similar properties. In silico analysis with PolyPhen-2 predicts the variant to be possibly damaging, but tolerated by SIFT. Mutation Taster predicts this variant to be disease causing. The glutamate at codon 1902 is conserved across species, as are neighboring amino acids. No other variants have been reported in association with disease at this codon and nearby codons. In total the variant has not been seen in ~6,000 published controls and individuals from publicly available population datasets. There is no variation at codon 1902 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,000 Caucasian and African American individuals (as of 5/15/13). Note that this dataset does not match the patient's ancestry (FIlipino). Based on data from the 1000 genomes project, the C-allele has an overal frequency of approximately 0.09% (2/2189). This amino acid position is well conserved on sequence alignment. The observed C-allele occurred in the Japanese population at a frequency of 1.12% (2/179). -

not provided Uncertain:2

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

Cardiomyopathy Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 03, 2021	- -
Likely benign, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Mar 22, 2021	The c.5704G>C (p.Glu1902Gln) variant in MYH7 has been identified in 0.096% (FAF 95% CI; 27/19954) of East Asian chromosomes in gnomAD v2.1.1 (https://gnomad.broadinstitute.org), which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BS1; Kelly 2018 PMID:29300372). Allowing a variant to reach a likely benign classification based on BS1 alone represents a revision of the original ACMG/AMP framework by ClinGen’s Sequence Variant Interpretation Working Group (Tavtigian 2018 PMID: 29300386). In summary, this variant meets criteria to be classified as likely benign for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): BS1 -

Hypertrophic cardiomyopathy Benign:2

Likely benign, criteria provided, single submitter	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Feb 07, 2018	MYH7 Glu1902Gln has been previously identified in HCM patients (Walsh R, et al., 2017; Chiou KR, et al., 2015), as well as a patient with heart failure and atrioventricular block (Liu N, et al., 2017). We identified this variant in a HCM proband of Korean descent. The proband has no family history of disease or sudden death. The variant is present in the Exome Aggregation Consortium dataset (MAF= 0.00007 http://exac.broadinstitute.org/) as well as the Genome Aggregation Database (MAF=0.000087), and is particularly common in East Asian populations (AF= 0.0001, http://gnomad.broadinstitute.org/). In silico tools MutationTaster and PolyPhen-2 predict this variant to be deleterious, however SIFT predicts this variant to be "Tolerated". In summary, although the variant has been identified in HCM cases these are likely to be incidental findings as the variant is present at a higher than expected frequency in the general population, furthermore in silico predictions are conflicting, therefore we classify MYH7 Glu1902Gln as 'likely benign' -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 20, 2023	- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 04, 2020

The p.E1902Q variant (also known as c.5704G>C), located in coding exon 37 of the MYH7 gene, results from a G to C substitution at nucleotide position 5704. The glutamic acid at codon 1902 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in an individual with hypertrophic cardiomyopathy (HCM), an atrioventricular block case with left ventricular hypertrophy, and in HCM genetic testing cohorts; however, in some cases clinical details were limited and/or additional cardiac variants were detected (Chiou KR et al. J Cardiol, 2015 Mar;65:250-6; Walsh R et al. Genet. Med., 2017 02;19:192-203; Liu N et al. Sci Rep, 2017 09;7:10676). 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. -

Dilated cardiomyopathy 1S Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

MYH7-related skeletal myopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Myosin storage myopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Left ventricular noncompaction cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

MYH7-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 25, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hypertrophic cardiomyopathy 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
CardioboostCm	Pathogenic	0.98
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Uncertain	0.070
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.15	T
MetaSVM	Uncertain	0.28	D
MutationAssessor	Pathogenic	3.0	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.9	N
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.10	T
Polyphen		0.74	P
Vest4		0.64
MVP		0.90
MPC		1.3
ClinPred		0.35	T
GERP RS		5.6
Varity_R		0.27
gMVP		0.97

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: rs187073962; hg19: chr14-23883054;