chr14-23431589-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PS4_SupportingPP3PM2

This summary comes from the ClinGen Evidence Repository: The c.728G>A (p.Arg243His) variant in MYH7 has been identified in 3 individuals with HCM (Arad 2005 PMID:16267253; van Velzen 2016 PMID:27476098; GeneDx pers. comm.), 2 individuals with DCM (one of whom carried a VUS in another DCM gene; Walsh 2017 PMID:27532257; GeneDx pers. comm.), 1 individual with LVNC, dilation, and congestive heart failure prior to transplant at 26 yo - Klaassen 2008 PMID:18506004) and 6 individuals with LVNC or non-compaction cardiomyopathy (van Waning 2018 29447731; Walsh 2017 PMID:27532257; GeneDx pers. comm.; Invitae pers. comm.). This variant segregated in 7 individuals with LVNC, 1 with LV dysfunction, and 1 with DCM from 5 families (Klaassen et al 2008, PMID 18506004; GeneDx, pers. comm.; Invitae, pers. comm.; OMGL, pers. comm.). While this variant has been reported in multiple phenotypes, there is conflicting evidence on whether isolated LVNC is a Mendelian disease and therefore those cases without additional cardiomyopathy features are not currently being counted. Therefore, the PS4_Supporting criterion is being applied for the DCM phenotypes. Additionally, current evidence is insufficient to establish segregation with DCM or HCM and therefore the PP1 criterion has not been applied. This variant was identified in 0.003% (1/34592) of Latino chromosomes in gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and while missense variants in this region are statistically more likely to be associated with HCM (Walsh 2017 PMID:27532257), location in this region cannot be used to support pathogenicity for other phenotypes that are predominant for this variant; therefore PM1 is not applicable. Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to variable and conflicting evidence, this variant is classified as uncertain significance for inherited cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting, PM2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA016701/MONDO:0004994/002

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:9U:3

Conservation

PhyloP100: 7.74

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4 link	c.728G>A	p.Arg243His	missense_variant	Exon 8 of 40	ENST00000355349.4	NP_000248.2	P12883
MYH7	NM_001407004.1 link	c.728G>A	p.Arg243His	missense_variant	Exon 7 of 39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4 link	c.728G>A	p.Arg243His	missense_variant	Exon 8 of 40	1	NM_000257.4	ENSP00000347507.3		P12883

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251492

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135920

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00000275

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:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:9Uncertain:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cardiomyopathy

Pathogenic:1Uncertain:2

Nov 30, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2022

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 16, 2021

ClinGen Cardiomyopathy Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The c.728G>A (p.Arg243His) variant in MYH7 has been identified in 3 individuals with HCM (Arad 2005 PMID:16267253; van Velzen 2016 PMID:27476098; GeneDx pers. comm.), 2 individuals with DCM (one of whom carried a VUS in another DCM gene; Walsh 2017 PMID:27532257; GeneDx pers. comm.), 1 individual with LVNC, dilation, and congestive heart failure prior to transplant at 26 yo - Klaassen 2008 PMID:18506004) and 6 individuals with LVNC or non-compaction cardiomyopathy (van Waning 2018 29447731; Walsh 2017 PMID:27532257; GeneDx pers. comm.; Invitae pers. comm.). This variant segregated in 7 individuals with LVNC, 1 with LV dysfunction, and 1 with DCM from 5 families (Klaassen et al 2008, PMID 18506004; GeneDx, pers. comm.; Invitae, pers. comm.; OMGL, pers. comm.). While this variant has been reported in multiple phenotypes, there is conflicting evidence on whether isolated LVNC is a Mendelian disease and therefore those cases without additional cardiomyopathy features are not currently being counted. Therefore, the PS4_Supporting criterion is being applied for the DCM phenotypes. Additionally, current evidence is insufficient to establish segregation with DCM or HCM and therefore the PP1 criterion has not been applied. This variant was identified in 0.003% (1/34592) of Latino chromosomes in gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and while missense variants in this region are statistically more likely to be associated with HCM (Walsh 2017 PMID:27532257), location in this region cannot be used to support pathogenicity for other phenotypes that are predominant for this variant; therefore PM1 is not applicable. Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to variable and conflicting evidence, this variant is classified as uncertain significance for inherited cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting, PM2, PP3. -

Hypertrophic cardiomyopathy

Pathogenic:2

Aug 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 243 of the MYH7 protein (p.Arg243His). This variant is present in population databases (rs267606910, gnomAD 0.003%). This missense change has been observed in individuals with left ventricular non-compaction cardiomyopathy (LVNC) (PMID: 18506004, 20965760, 21551322). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14126). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). For these reasons, this variant has been classified as Pathogenic. -

Apr 20, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg243His variant in MYH7 has been reported in 1 individual with hypertrop hic cardiomyopathy (Arad 2005), 1 with Ebstein anomaly (Sicko 2016), and 1 with left ventricular non-compaction, where it segregated in two affected relatives ( Klaassen 2008). It has been identified in 1/111714 European chromosomes by the G enome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs2 67606910) and has been reported in ClinVar (Variation ID: 14126). In addition, another amino acid substitution involving this codon, p.Arg243Cys, has also been identified in individuals with HCM (Kubo 2011, Homburger 2016, Viswanathan 2017 ). Computational prediction tools and conservation analysis suggest that the p.A rg243His variant may impact the protein, though this information is not predicti ve enough to determine pathogenicity. This variant lies in the head region of th e protein and missense variants in this region have been reported and statistica lly indicated to be more likely to cause disease (Walsh 2016). In summary, altho ugh additional studies are required to fully establish its clinical significance , the p.Arg243His variant is likely pathogenic. ACMG/AMP Criteria applied: PM1; PM2; PM5; PP3. -

Hypertrophic cardiomyopathy 1

Pathogenic:2

Aug 01, 2017

Phosphorus, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 03, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:1Uncertain:1

Apr 19, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 23, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); 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: 27066506, 21551322, 27532257, 20031619, 24268868, 28606303, 26183555, 16267253, 20965760, 27247418, 29447731, 21310275, 12749056, 32233023, 29300372, 33500567, 34819141, 30275503, 35931685, 35216312, 37652022, 27476098, 27788187, 31447099, 34540771, 37842866, 18506004) -

Wolff-Parkinson-White pattern

Pathogenic:1

Jul 14, 2017

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

This variant was identified in an individual with Wolff-Parkinson-White syndrome -

Left ventricular noncompaction 5

Pathogenic:1

Jun 03, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Cardiovascular phenotype

Pathogenic:1

Mar 18, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R243H variant (also known as c.728G>A), located in coding exon 6 of the MYH7 gene, results from a G to A substitution at nucleotide position 728. The arginine at codon 243 is replaced by histidine, an amino acid with highly similar properties. This alteration has been detected in multiple individuals with left ventricular noncompaction (LVNC) and has been reported to segregate with disease in families (Klaassen S et al. Circulation, 2008 Jun;117:2893-901; Chang B et al. Mol. Genet. Metab., 2011 Feb;102:200-6; van Waning JI et al. J. Am. Coll. Cardiol., 2018 Feb;71:711-722; Coban-Akdemir ZH et al. Am J Med Genet A, 2020 06;182:1387-1399; external communication). This variant has also been identified in patients with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) (Arad M et al. Circulation, 2005 Nov;112:2805-11; external communication). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

CardioboostCm

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

Eigen

Pathogenic

0.83

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.98

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.0

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-4.1

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

1.0

MutPred

0.86

Gain of catalytic residue at D239 (P = 0.0138);

MVP

0.99

MPC

2.3

ClinPred

0.99

GERP RS

3.5

Varity_R

0.85

gMVP

0.99

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