chr14-23415757-G-A

Position:

chr14-23415757-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM5PP2PP3_Strong

The NM_000257.4(MYH7):c.5029C>T(p.Arg1677Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,461,888 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. R1677H) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:5

Conservation

PhyloP100: 1.72

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 Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a helix (size 50) in uniprot entity MYH7_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) in NM_000257.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr14-23415756-C-T is described in Lovd as [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, 0.96

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MYH7	NM_000257.4 linkuse as main transcript	c.5029C>T	p.Arg1677Cys	missense_variant	35/40	ENST00000355349.4	NP_000248.2
MHRT	NR_126491.1 linkuse as main transcript	n.189G>A		non_coding_transcript_exon_variant	2/6
MYH7	NM_001407004.1 linkuse as main transcript	c.5029C>T	p.Arg1677Cys	missense_variant	34/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.5029C>T	p.Arg1677Cys	missense_variant	35/40	1	NM_000257.4	ENSP00000347507	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251376

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135874

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727244

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:

0.0000189

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Nov 30, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 04, 2023	This missense variant replaces arginine with cysteine at codon 1677 of the MYH7 protein. Computational prediction suggests that this variant may have 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 one individual affected with hypertrophic cardiomyopathy (PMID: 27532257). This variant was also reported in one individual affected with dilated cardiomyopathy (PMID: 29773157). This variant has also been reported in compound heterozygous state with p.Gln44* in two siblings affected with left ventricular non-compaction cardiomyopathy (PMID: 30924982). Their parents were heterozygous carriers of either mutation and showed no clinical symptoms. This variant has been identified in 3/251376 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. -

Hypertrophic cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 11, 2023

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1677 of the MYH7 protein (p.Arg1677Cys). This variant is present in population databases (rs377461670, gnomAD 0.002%). This missense change has been observed in individuals with clinical features of MYH7-related cardiomyopathy (PMID: 27532257, 30924982; Invitae). ClinVar contains an entry for this variant (Variation ID: 181270). 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%. For these reasons, this variant has been classified as Pathogenic. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jan 14, 2021

Variant summary: MYH7 c.5029C>T (p.Arg1677Cys) 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 1.2e-05 in 251376 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5029C>T has been reported in the literature in individuals affected with Cardiomyopathy (Kolokotronis_2019, Walsh_2016, Ware_2018). These reports however, 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. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 21, 2020

Reported in two children with left ventricular non-compaction cardiomyopathy who also had a novel MYH7 Q44X variant in trans, the parent harboring R1677C had mild septal hypertrophy (Kolokotronis et al., 2019) and in a patient referred for HCM genetic testing (Walsh et al., 2017); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect This variant is associated with the following publications: (PMID: 30924982, 21750094, 27532257) -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 27, 2022

The p.R1677C variant (also known as c.5029C>T), located in coding exon 33 of the MYH7 gene, results from a C to T substitution at nucleotide position 5029. The arginine at codon 1677 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was detected in a patient referred for hypertrophic cardiomyopathy genetic testing; however, clinical details were limited (Walsh R et al. Genet Med. 2017;19:192-203). This variant has also been reported in a dilated cardiomyopathy (DCM) cohort (Ware JS et al. J Am Coll Cardiol, 2018 05;71:2293-2302). This alteration was also detected in siblings with left ventricular non-compaction (LVNC) who also carried a nonsense alteration in MYH7 (Kolokotronis K et al. Hum Mutat, 2019 08;40:1101-1114). Another variant affecting this codon (p.R1677H) has been reported in cardiomyopathy cohorts; however clinical details are limited (Waldmüller S et al. Eur J Heart Fail. 2011;13:1185-92). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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

Uncertain

0.56

CardioboostCm

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.91

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

0.96

MetaSVM

Pathogenic

0.80

MutationAssessor

Pathogenic

4.3

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-5.1

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.88

MVP

0.95

MPC

1.8

ClinPred

1.0

GERP RS

4.4

Varity_R

0.48

gMVP

0.82

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