chr14-23424875-C-T

Position:

chr14-23424875-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM5PP2PP3PP5

The NM_000257.4(MYH7):c.2573G>A(p.Arg858His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,614,226 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R858G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:3

Conservation

PhyloP100: 0.761

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 Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_000257.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr14-23424876-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 164324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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, 0.816

PP5

Variant 14-23424875-C-T is Pathogenic according to our data. Variant chr14-23424875-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 177696.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=3}. Variant chr14-23424875-C-T is described in Lovd as [Pathogenic]. Variant chr14-23424875-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4 linkuse as main transcript	c.2573G>A	p.Arg858His	missense_variant	22/40	ENST00000355349.4
MYH7	NM_001407004.1 linkuse as main transcript	c.2573G>A	p.Arg858His	missense_variant	21/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.2573G>A	p.Arg858His	missense_variant	22/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152220

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251456

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000150

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152338

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.0000240

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 30, 2021	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 858 of the MYH7 protein (p.Arg858His). This variant is present in population databases (rs2856897, gnomAD 0.007%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 15563892, 27532257, 31980526). ClinVar contains an entry for this variant (Variation ID: 177696). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 01, 2020	The p.Arg858His variant in MYH7 has been identified in at least 4 individuals with HCM (Song 2005, Berge 2014, Walsh 2017, LMM data) and was identified in 3/251456 chromosomes by gnomAD (https://gnomad.broadinstitute.org). It has also been reported in ClinVar (Variation ID #177696). Computational prediction tools and conservation analysis suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. Of note, 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 2016). In addition, another variant involving this amino acid, p.Arg858Cys, has been classified as pathogenic by this laboratory. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg858GHis variant is likely pathogenic. ACMG/AMP Criteria applied: PM1, PM2, PM5, PS4_Supporting, BP4. -

Cardiomyopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Oct 02, 2021

This missense variant replaces arginine with histidine at codon 858 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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: 15563892, 24111713, 25351510, 27532257, 28759816, 31980526). This variant has been identified in 3/251456 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same codon, p.Arg858Cys and p.Arg858Pro, are known to be disease-causing (ClinVar variation ID: 164324, 520277). Based on the available evidence, this variant is classified as Likely Pathogenic. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 06, 2022

Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in ClinVar (ClinVar Variant ID# 177696; ClinVar); This variant is associated with the following publications: (PMID: 22763267, 15563892, 27532257, 27247418, 25351510, 26332594, 24111713, 23403236, 31980526, 34426522, 29300372) -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 15, 2023

Variant summary: MYH7 c.2573G>A (p.Arg858His) results in a non-conservative amino acid change located in the Myosin tail (IPR002928) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251456 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2573G>A has been reported in the literature in individuals affected with Cardiomyopathy (example, Song_2005, Gandjbakhch_2010, Olfson_2015, Hou_2020, Stava_2022, Kurzlechner_2022, Dai_2021, Rijdt_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Additionally, several missense variants at the Arg858 residue have been reported in individuals with Cardiomyopathy, among which, p.Arg858Cys may be associated with disease (ClinVar ID: 164324), suggesting that this codon may be functionally important. The following publications have been ascertained in the context of this evaluation (PMID: 34333030, 22763267, 31980526, 35629155, 26332594, 28759816, 15563892, 35653365). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=2; Likely pathogenic, n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 07, 2024

The p.R858H variant (also known as c.2573G>A), located in coding exon 20 of the MYH7 gene, results from a G to A substitution at nucleotide position 2573. The arginine at codon 858 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 hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited (Song L et al. Clin. Chim. Acta. 2005;351:209-16; Golbus JR et al. Circ Cardiovasc Genet. 2012;5:391-9; Berge KE and Leren TP. Clin. Genet. 2014;86:355-60; Lopes LR et al. Heart. 2015;101:294-301; Walsh R et al. Genet. Med. 2017;19:192-203). This amino acid position is not well 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

CardioboostCm

Uncertain

0.25

BayesDel_addAF

Uncertain

0.082

BayesDel_noAF

Uncertain

0.060

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.061

LIST_S2

Uncertain

0.92

M_CAP

Pathogenic

0.46

MetaRNN

Pathogenic

0.82

MetaSVM

Uncertain

0.043

MutationAssessor

Benign

1.5

MutationTaster

Benign

0.77

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-2.2

REVEL

Uncertain

0.53

Sift

Uncertain

0.012

Sift4G

Uncertain

0.043

Polyphen

0.0080

Vest4

0.80

MVP

0.86

MPC

1.2

ClinPred

0.56

GERP RS

3.8

Varity_R

0.21

gMVP

0.89

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