14-23416140-C-T

Position:

chr14-23416140-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM5PP2PP3_Moderate

The NM_000257.4(MYH7):c.4817G>A(p.Arg1606His) variant causes a missense change. The variant allele was found at a frequency of 0.0000409 in 1,614,048 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1606C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:14

Conservation

PhyloP100: 4.64

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:

MHRT (HGNC:):

MHRT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr14-23416141-G-A is described in Lovd as [Likely_pathogenic].

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, 0.911

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH7	NM_000257.4 linkuse as main transcript	c.4817G>A	p.Arg1606His	missense_variant	34/40	ENST00000355349.4	NP_000248.2	P12883
MYH7	NM_001407004.1 linkuse as main transcript	c.4817G>A	p.Arg1606His	missense_variant	33/39		NP_001393933.1
MHRT	NR_126491.1 linkuse as main transcript	n.401C>T		non_coding_transcript_exon_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.4817G>A	p.Arg1606His	missense_variant	34/40	1	NM_000257.4	ENSP00000347507.3		P12883

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000478

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251484

Hom.:

AF XY:

0.0000441

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000703

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000431

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

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:

0.0000522

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

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:

0.000478

Alfa

AF:

0.000138

Hom.:

Bravo

AF:

0.0000264

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 06, 2024	Reported in association with hypertrophic cardiomyopathy (PMID: 27247418, 24093860, 24793961, 25351510, 27532257, 28771489); 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: 24093860, 28771489, 25351510, 24793961, 25031304, 27532257, 34542152, 37652022, 33495597, 34495297, 27247418) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 09, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 02, 2019	The p.Arg1606His variant in MYH7 has been reported in 8 individuals with HCM (Marsiglia 2013, Helms 2014, Bos 2014, Lopes 2015, Walsh 2017, LMM data), one of whom carried a pathogenic variant in MYH7 that was sufficient to cause disease (LMM data). This variant has also been reported in ClinVar (Variation ID 43039) and in 0.007% (9/126718) European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Arg1606His variant is uncertain. ACMG/AMP Criteria Applied: PP3 -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Apr 04, 2013	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.Arg1606His (c.4817 G>A) in the MYH7 gene. Based on the data reviewed below, we too classify this variant as of unknown clinical significance. The variant appears to be novel. As of November 2011, no variation at codon 1606 of MYH7 has been reported in the literature either in association with disease or as a benign polymorphism (according to searches of PubMed and Google). No variation at this codon is found in the following databases: NHLBI Exome Sequencing Project; dbSNP; 1000 Genomes; the Harvard Sarcomere Protein Gene Mutation Database; or UniProt. Furthermore, these databases report no missense variants within 10 amino acids to either side of this location. This variant has also not been seen in 200 Caucasian and African American presumably healthy controls tested at GeneDx. The Arginine at position 1606 is completely conserved across species. However, in silico analysis (PolyPhen-2) predicts the variant to be “benign.” This is a chemically conservative amino acid change. The variant substitutes one positively charged amino acid (Arg) with another positively charged amino acid (His). -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 26, 2024	Variant summary: MYH7 c.4817G>A (p.Arg1606His) results in a non-conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251484 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MYH7 causing Cardiomyopathy (4e-05 vs 0.0013), allowing no conclusion about variant significance. c.4817G>A has been reported in the literature in individuals affected with hypertrophic cardiomyopathy and Early-Onset Atrial Fibrillation, without strong evidence for causality (examples, Marsiglia_2013, Homburger_2016, Walsh_2017, Yoneda_2021, Park_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Helms_2014). The following publications have been ascertained in the context of this evaluation (PMID: 25031304, 27247418, 24093860, 34542152, 27532257, 34495297). ClinVar contains an entry for this variant (Variation ID: 43039). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hypertrophic cardiomyopathy 1

Pathogenic:1Uncertain:1

Likely pathogenic, flagged submission	clinical testing	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 05, 2019	The MYH7 c.4817G>A (p.Arg1606His) missense variant has been reported in two studies in which it is identified in a heterozygous state in at least five unrelated individuals with hypertrophic cardiomyopathy (Marsiglia et al. 2013; Walsh et al. 2017). Family history information was unavailable for the affected individuals. Control data are unavailable for this variant which is reported at a frequency of 0.000075 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the limited evidence, the p.Arg1606His variant is classified as a variant of uncertain significance but suspicious for pathogenicity for hypertrophic cardiomyopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 23, 2023	This missense variant replaces arginine with histidine at codon 1606 of the MYH7 protein. Computational prediction suggests that this variant may have a 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 individuals affected with hypertrophic cardiomyopathy (PMID: 24093860, 25031304, 27247418, 27532257, 28640247, 28771489, 29875424, 30297972, 33495597). This variant has been identified in 11/282872 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	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 06, 2023	- -

Arrhythmogenic right ventricular cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Feb 02, 2017

- -

Primary familial hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Jun 27, 2017

- -

Hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1606 of the MYH7 protein (p.Arg1606His). This variant is present in population databases (rs373514686, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of hypertrophic cardiomyopathy (PMID: 24093860, 25031304, 25351510, 27247418, 27532257, 28771489). ClinVar contains an entry for this variant (Variation ID: 43039). 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. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 04, 2022

The c.4817G>A (p.R1606H) alteration is located in exon 34 (coding exon 32) of the MYH7 gene. This alteration results from a G to A substitution at nucleotide position 4817, causing the arginine (R) at amino acid position 1606 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

CardioboostCm

Pathogenic

0.94

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.83

Eigen

Pathogenic

0.75

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.91

MetaSVM

Uncertain

0.73

MutationAssessor

Pathogenic

3.8

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.0

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.023

Polyphen

1.0

Vest4

0.67

MVP

0.98

MPC

1.7

ClinPred

0.96

GERP RS

4.5

Varity_R

0.36

gMVP

0.65

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