14-23431789-C-T

Position:

chr14-23431789-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PM1PP1PS4

This summary comes from the ClinGen Evidence Repository: The NM_000257.4(MYH7):c.611G>A (p.Arg204His) variant has been identified in at least >45 individuals with HCM, at least 7 of whom had disease-causing variants in other cardiomyopathy associated genes (PS4; Richard 2003 PMID:12707239; Funada 2010 PMID:20975235; Berge 2014 PMID:24111713; Homburger 2016 PMID:27247418; Ntusi 2016 PMID:27841901; Walsh 2017 PMID:27532257; Burns 2017 PMID:28790153; Mattivi 2020 PMID:32894683; Ambry pers. comm.; Centenary Institute Sydney pers. comm.; CHEO pers. comm.; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant segregated with HCM in 4 affected relatives from 4 families (PP1; GeneDx pers. comm.; OMGL pers. comm.). This variant was identified in 0.0006% (FAF 95% CI; 3/129190) of European chromosomes by gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis did not provide evidence for or against an impact to the protein. In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4, PP1, PM2, PM1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA016546/MONDO:0005045/002

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14U:2

Conservation

PhyloP100: 3.66

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.

PS4

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

PM1

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

PM2

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

PP1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH7	NM_000257.4 linkuse as main transcript	c.611G>A	p.Arg204His	missense_variant	7/40	ENST00000355349.4	NP_000248.2	P12883
MYH7	NM_001407004.1 linkuse as main transcript	c.611G>A	p.Arg204His	missense_variant	6/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.611G>A	p.Arg204His	missense_variant	7/40	1	NM_000257.4	ENSP00000347507.3		P12883

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152240

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251488

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000150

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727248

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:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74376

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:2

Likely pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Sep 24, 2014	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. Review of data on p.Arg204His in MYH7 Summary: -Seen in at least 20 presumably unrelated cases of HCM (5 published, 15 unpublished). -3 of 20 cases who had sequencing of at least MYH7 and MYBPC3 had another sarcomere variant: -----Late 50s female with HCM and fhx of CHF and sudden death, carried another MYH7 variant (classified as likely pathogenic by LMM) -----Late 30s female with HCM and fhx of sudden death, carried an MYBPC3 variant (frameshift variant, LMM classified as pathogenic) -----Woman diagnosed at 72yo with LVWT 15 mm and an MYL2 variant (GeneDx classifies as variant of uncertain significance) -3 of 20 cases had an additional variant in a non-sarcomere gene: -----A 53yo male with LVWT 20 mm and a daughter with HCM carried a variant of uncertain significance in MTTG -----A patient carried a variant in MuRF2 that the authors hypothesize is a modifier -----Late 40s female with LVH and NSVT and fhx of “possible HCM/enlarged heart and sudden death, and carried a variant in PKP2 (-1 splice variant, LMM classified as likely pathogenic) -There is weak segregation data. In at least one family an additional affected relative carried this variant. -The variant was not observed in a total of ~61,161 individuals from published controls and publicly available datasets that were not selected for HCM. Published cases: Richard et al. (2003) reported this variant in one out of 197 patients diagnosed with HCM that were cared for in Paris, France, who underwent analysis of the MYH7, MYBPC3, MYL2, MYL3, TNNI3, and TNNT2 genes. This case is most likely redundant with a later report by the same group (Gandjbakhch et al. 2010). Meyer et al. (2013) reported this variant in one out of 8 patients diagnosed with HCM that were cared for in Marburg, Germany, who underwent analysis of MYH7 and MYBPC3. No other phenotypic information was reported in the paper. Berge et al. (2014) reported this variant in one out of 696 patients diagnosed with HCM that were cared for in Norway, who underwent analysis of the MYH7, MYBPC3, TNNI3, TNNT2, MYL2, and MYL3 genes. No other phenotypic information was reported in the paper. Su et al. (2014) reported this variant in 2 patients diagnosed with HCM that were cared for in Beijing, China, who underwent analysis of MYH7, MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1, MuRF1, MuRF2, and MuRF3 genes. One of the two patients carries a second variant in MuRF2 gene (c.1516A>T; p.T506S). Authors propose that rare variants in MuRF2 genes increase the risk of development of HCM and lead to more severe disease phenotypes, and thus may act as modifiers of the disease. This variant substitutes a polar, positively charged amino acid (Arg) with a polar, positively charged amino acid (His). In silico analysis with PolyPhen-2 predicts the variant to be “possibly damaging” and SIFT predicts the variant to be “deleterious.” The Arginine at codon 204 is moderately conserved across species, as are neighboring amino acids. It is highly conserved among mammals. Other variants have been reported in association with disease at this codon (c.610C>T (p.Arg204Cys) with classification as pathogenic by GeneDx in ClinVar, no other submitters; c.611G>T (p.Arg204Leu) with conflicting classifications in ClinVar) and nearby codons (p.Ala199Val; p.Ile201Thr (Villard, 2005); p.Lys207Gln (Mohiddin, 2003)). The variant was not observed in ~61,113 individuals from published controls and publicly available datasets that approximate the general population. This includes ~60,706 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of -
Uncertain significance, flagged submission	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, flagged submission	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2024	Reported in a patient with early-onset atrial fibrillation in published literature (PMID: 34495297); Identified in a patient with clinically diagnosed limb-girdle muscular dystrophy (LGMD) who harbored an additional pathogenic variant in the CAPN3 gene (PMID: 29970176); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20439259, 24865491, 12707239, 27532257, 27247418, 24111713, 27841901, 20975235, 23074333, 23816408, 28986452, 28790153, 32894683, 35982159, 31843643, 34542152, 35653365, 37377035, 36243179, 34495297, 29970176, 29300372, 37652022) -

Hypertrophic cardiomyopathy 1

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jan 06, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000043095, PMID:12707239, PS1_S). A different missense change at the same codon has been reported to be associated with MYH7 related disorder (PMID:27247418, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.655, 3CNET: 0.958, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000018, PM2_M). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 05, 2022	- -

Myosin storage myopathy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 05, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 05, 2022	- -

Hypertrophic cardiomyopathy

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 29, 2021	The p.Arg204His variant in MYH7 has been observed in >20 probands with hypertrophic cardiomyopathy (HCM) and segregated with disease in at least 1 affected family member (Richard 2003 PMID: 12707239, Meyer 2013 PMID: 23816408, Su 2014 PMID: 24865491, Berge 2014 PMID: 24111713, Ntusi 2016 PMID: 27841901, Furqan 2017 PMID: 28986452, Walsh 2017 PMID: 27532257, LMM data). At least 5 of the affected individuals carried additional disease-causing variants cardiomyopathy associated genes that may have also contributed to their phenotypes (Furqan 2017, LMM data). This variant has been reported by other clinical laboratories in ClinVar (Variation ID 43095). It has also been identified in 0.0023% (3/129190) of European chromosomes in gnomAD (https://gnomad.broadinstitute.org). This variant lies in the head region of the protein and missense variants in this region are statistically more likely to be disease-associated (Walsh 2017 PMID: 27532257). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP criteria applied: PS4, PM1, PM2_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 204 of the MYH7 protein (p.Arg204His). This variant is present in population databases (rs397516260, gnomAD 0.005%). This missense change has been observed in individuals with autosomal dominant hypertrophic cardiomyopathy (PMID: 12707239, 23816408, 24111713, 24865491, 27247418, 27532257, 27841901). ClinVar contains an entry for this variant (Variation ID: 43095). 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%. 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. -

Dilated cardiomyopathy 1S

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 05, 2022

- -

Cardiomyopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Mar 29, 2023

The c.611G>A variant in MYH7 causes an amino acid substitution, which replaces arginine with histidine at position 204. It was identified in 5/282888 (0.0003%) of alleles tested from control populations in the Genome Aggregation Database (gnomAD), including in 0.005% of alleles tested from the East Asian population, and is neither sufficiently rare to provide evidence in favor of pathogenicity nor sufficiently common to provide evidence against pathogenicity. It has been previously reported in at least 15 apparently unrelated individuals with hypertrophic cardiomyopathy (PMID 12707239, 20975235, 23074333, 23816408, 24111713, 24865491, 27532257, 27841901, 28986452, and others). This variant was reported to segregate with disease in one family (PMID 28986452). This variant is located within the head region (codons 181-937) of the Myosin-7 protein (NM_000257.2; NP_000248.2), where MYH7 pathogenic variants are significantly clustered (PMID 29300372). Alternate amino acid substitutions have been previously established as pathogenic at the 204 residue, c.611G>T, p.Arg204Leu, in patients with hypertrophic cardiomyopathy (PMID 27532257, ClinVar database). The Arg204 residue is highly conserved across evolutionarily distant species. In silico analysis programs (SIFT, PolyPhen-2, Mutation Taster) predict this variant to have an impact on the protein function. This variant is listed in ClinVar (VCV000043095). Based on the above information, we categorize this variant as likely pathogenic. -

MYH7-related skeletal myopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 05, 2022

- -

Myopathy, myosin storage, autosomal recessive

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 05, 2022

- -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2024

The p.R204H variant (also known as c.611G>A), located in coding exon 5 of the MYH7 gene, results from a G to A substitution at nucleotide position 611. The arginine at codon 204 is replaced by histidine, an amino acid with highly similar properties. This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (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 has been reported in a number of hypertrophic cardiomyopathy (HCM) cohorts and in individuals with features consistent with HCM (Richard P et al. Circulation. 2003;107:2227-32; Funada A et al. Circ. J. 2010;74:2674-80; Meyer T et al. Gene. 2013;527:416-20; Berge KE et al. Clin. Genet. 2014;86:355-60; Su M et al. Int J Mol Sci. 2014;15:9302-13; Ntusi NA et al. Cardiovasc J Afr. 2016;27:152-158; Burns C et al. Circ Cardiovasc Genet. 2017;10:e001666; Walsh R et al. Genet. Med. 2017;19:192-203; Ambry internal data). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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

Benign

0.23

CardioboostCm

Pathogenic

0.92

BayesDel_addAF

Uncertain

0.089

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.65

Eigen

Benign

0.11

Eigen_PC

Benign

0.092

FATHMM_MKL

Benign

0.62

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.84

MetaRNN

Pathogenic

0.88

MetaSVM

Uncertain

0.14

MutationAssessor

Benign

0.96

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.1

REVEL

Pathogenic

0.66

Sift

Uncertain

0.013

Sift4G

Uncertain

0.029

Polyphen

0.96

Vest4

0.76

MutPred

0.66

Gain of catalytic residue at A199 (P = 0.0019);

MVP

0.93

MPC

1.8

ClinPred

0.85

GERP RS

3.1

Varity_R

0.36

gMVP

0.60

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