rs397516260

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PM5PP2PP5_Very_StrongBP4

The NM_000257.4(MYH7):c.611G>T(p.Arg204Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,614,134 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 pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R204C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8U: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 Pathogenic. Variant got 10 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr14-23431790-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.

PP5

Variant 14-23431789-C-A is Pathogenic according to our data. Variant chr14-23431789-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 177869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.4036721). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH7	NM_000257.4 linkuse as main transcript	c.611G>T	p.Arg204Leu	missense_variant	7/40	ENST00000355349.4	NP_000248.2	P12883
MYH7	NM_001407004.1 linkuse as main transcript	c.611G>T	p.Arg204Leu	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>T	p.Arg204Leu	missense_variant	7/40	1	NM_000257.4	ENSP00000347507.3		P12883

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152242

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00

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:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74378

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Mar 06, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 12, 2024	Reported in association with hypertrophic cardiomyopathy (HCM) or unexplained cardiac arrest in individuals referred for genetic testing at GeneDx and in published literature; detailed clinical and segregation data were often not provided (PMID: 27532257, 33673806, 35352813, 37652022); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24111713, 27247418, 27841901, 21310275, 12707239, 33673806, 35352813, 27532257, 37652022, 26338694, 29300372) -
Uncertain significance, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Dec 03, 2015	- -

Cardiomyopathy

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	May 18, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jan 20, 2023	- -

Hypertrophic cardiomyopathy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 14, 2023	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 204 of the MYH7 protein (p.Arg204Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 177869). An algorithm developed specifically for the MYH7 gene suggests that this missense change is likely to be tolerated (PMID: 21310275). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jun 08, 2023	This missense variant replaces arginine with leucine at codon 204 of the MYH7 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 27532257, 35352813, communication with external laboratories: SCV000749807.7, SCV000208685.13). It. has also been reported in an individual affected with sudden cardiac death and suspected cardiomyopathy (PMID: 35352813). A different variant occurring at the same codon, p.Arg204His, is a considered to be disease-causing (Clinvar variation ID: 43095), indicating that arginine at this position is important for MYH7 protein function. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

MYH7-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 13, 2024

The MYH7 c.611G>T variant is predicted to result in the amino acid substitution p.Arg204Leu. This variant has been reported in several individuals with hypertrophic cardiomyopathy (HCM) (Table S1B, Walsh et al. 2017. PubMed ID: 27532257; Table S2, Hathaway et al. 2021. PubMed ID: 33673806; Table S8, McGurk et al. 2023. PubMed ID: 37652022). An alternate nucleotide change at the same genomic position (c.611G>A; p.Arg204His) has been reported in individuals with HCM (Richard et al. 2003. PubMed ID: 12707239; Berge et al. 2014. PubMed ID: 24111713). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 17, 2023

The p.R204L variant (also known as c.611G>T), located in coding exon 5 of the MYH7 gene, results from a G to T substitution at nucleotide position 611. The arginine at codon 204 is replaced by leucine, an amino acid with dissimilar 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 variant has been detected in four individuals from a hypertrophic cardiomyopathy (HCM) genetic testing cohort; however, clinical details were limited (Walsh R et al. Genet Med, 2017 02;19:192-203). Another alteration at the same codon, p.R204H (c.611G>A), has also been reported in association with HCM (Richard P et al. Circulation. 2003). 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. -

not specified

Uncertain:1

Uncertain significance, flagged submission

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 17, 2014

The Arg204Leu variant in MYH7 has not been reported in the literature, but has b een identified by our laboratory in 4 Caucasian individuals with HCM, one of who m also carried another variant of unknown significance in MYBPC3. This variant h as not been identified in large European American and African American populatio ns by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS); oth er populations have not been examined adequately. Arginine (Arg) at this positio n is conserved in mammals and chickens, but this part of the MYH7 protein appear s to be less well conserved in more distantly related species. In addition, this variant was predicted to be benign using a computational tool clinically valida ted by our laboratory. This tool's benign prediction is estimated to be correct 89% of the time (Jordan 2011). While the presence in multiple affected individua ls and absence from the general population are consistent with a role in disease , the computational data suggest that the variant may not impact the normal func tion of the protein. In summary, additional information is needed to fully asses s the clinical significance of the Arg204Leu variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

CardioboostCm

Uncertain

0.26

BayesDel_addAF

Uncertain

0.064

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.65

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.075

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.86

M_CAP

Pathogenic

0.75

MetaRNN

Benign

0.40

MetaSVM

Uncertain

-0.12

MutationAssessor

Benign

0.80

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.49

Sift

Benign

0.16

Sift4G

Benign

0.096

Polyphen

0.61

Vest4

0.24

MutPred

0.49

Gain of catalytic residue at A199 (P = 0.0031);

MVP

0.94

MPC

1.3

ClinPred

0.82

GERP RS

3.1

Varity_R

0.40

gMVP

0.80

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