rs377461670

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

16
3
1

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]
MHRT (HGNC:51291): (myosin heavy chain associated RNA transcript) This gene encodes a spliced long non-coding RNA that may act as a cardioprotective agent in the heart. Based on a study of a similar gene in mouse, the encoded transcript may regulate chromatin remodeling by acting as a decoy to the BRG1 chromatin repressor complex thus preventing it from binding to its genomic targets. Blocking the actions of BRG1 could be crucial in protecting the heart from pathological hypertrophy. [provided by RefSeq, Dec 2014]

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 the MYH7 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 341 curated pathogenic missense variants (we use a threshold of 10). The gene has 16 curated benign missense variants. Gene score misZ: 3.9329 (above the threshold of 3.09). Trascript score misZ: 6.7889 (above the threshold of 3.09). GenCC associations: The gene is linked to 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 rank MANE Protein UniProt
MYH7NM_000257.4 linkc.5029C>T p.Arg1677Cys missense_variant Exon 35 of 40 ENST00000355349.4 NP_000248.2 P12883
MYH7NM_001407004.1 linkc.5029C>T p.Arg1677Cys missense_variant Exon 34 of 39 NP_001393933.1
MHRTNR_126491.1 linkn.189G>A non_coding_transcript_exon_variant Exon 2 of 6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MYH7ENST00000355349.4 linkc.5029C>T p.Arg1677Cys missense_variant Exon 35 of 40 1 NM_000257.4 ENSP00000347507.3 P12883
ENSG00000258444ENST00000557368.1 linkn.*71G>A downstream_gene_variant 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251376
Hom.:
0
AF XY:
0.0000147
AC XY:
2
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:
24
AN:
1461888
Hom.:
0
Cov.:
34
AF XY:
0.0000110
AC XY:
8
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.:
32
Bravo
AF:
0.00000378
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000165
AC:
2
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
Oct 04, 2023
Color Diagnostics, LLC DBA Color Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Nov 30, 2021
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy Pathogenic:1
Dec 12, 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 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; internal data). ClinVar contains an entry for this variant (Variation ID: 181270). 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%. For these reasons, this variant has been classified as Pathogenic. -

not specified Uncertain:1
Jan 14, 2021
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Jul 21, 2020
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Jun 27, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
D
BayesDel_noAF
Pathogenic
0.35
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.91
D
Eigen
Pathogenic
0.83
Eigen_PC
Pathogenic
0.72
FATHMM_MKL
Uncertain
0.83
D
LIST_S2
Uncertain
0.96
D
M_CAP
Pathogenic
0.90
D
MetaRNN
Pathogenic
0.96
D
MetaSVM
Pathogenic
0.80
D
MutationAssessor
Pathogenic
4.3
H
PrimateAI
Pathogenic
0.93
D
PROVEAN
Pathogenic
-5.1
D
REVEL
Pathogenic
0.87
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.88
MVP
0.95
MPC
1.8
ClinPred
1.0
D
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.

Other links and lift over

dbSNP: rs377461670; hg19: chr14-23884966; COSMIC: COSV105912884; COSMIC: COSV105912884; API