14-23422189-C-T

Position:

chr14-23422189-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP2PP3

The NM_000257.4(MYH7):c.3236G>A(p.Arg1079Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,612,834 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1079W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 0.185

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 Uncertain_significance. Variant got 2 ACMG points.

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, 0.787

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4 linkuse as main transcript	c.3236G>A	p.Arg1079Gln	missense_variant	25/40	ENST00000355349.4
MYH7	NM_001407004.1 linkuse as main transcript	c.3236G>A	p.Arg1079Gln	missense_variant	24/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.3236G>A	p.Arg1079Gln	missense_variant	25/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251434

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135892

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:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1460746

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

726674

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152088

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000688

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cardiomyopathy

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Nov 08, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 20, 2023	This missense variant replaces arginine with glutamine at codon 1079 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 several unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 25611685, 27600940, 27532257, 33495597), dilated cardiomyopathy (PMID: 21750094), or systemic amyloidosis with a cardiac involvement (PMID: 24749114). This variant has also been reported in two families with hypertrophic cardiomyopathy, including three affected carriers and three unaffected carriers (PMID: 20359594, 28687478, 28790153). This variant has been identified in 2/282774 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 06, 2022	This missense variant replaces arginine with glutamine at codon 1079 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 several unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 25611685, 27600940, 27532257, 33495597), dilated cardiomyopathy (PMID: 21750094), or systemic amyloidosis with a cardiac involvement (PMID: 24749114). This variant has also been reported in two families with hypertrophic cardiomyopathy, including three affected carriers and three unaffected carriers (PMID: 20359594, 28687478, 28790153). This variant has been identified in 2/282774 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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 03, 2019

The p.Arg1079Gln variant in MYH7 has been identified in 3 individuals with cardiomyopathy (1 with DCM and 2 with HCM) and segregated with disease in one affected family member (WaldmÃ¼ller 2011, Cecconi 2016, LMM data). In addition, this variant was identified by our laboratory in 1 individual with HCM and 1 affected family member, who both also carried a pathogenic variant in MYBPC3. This variant has been identified in 2/129124 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID:177826). Computational prediction tools and conservation analysis suggest that the p.Arg1079Gln variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Arg1079Gln variant is uncertain. ACMG/AMP Criteria applied: PM2, PS4_Supporting, BP4. -

Congenital myopathy with fiber type disproportion

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Sep 22, 2019

This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PM2. -

Hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 02, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1079 of the MYH7 protein (p.Arg1079Gln). This variant is present in population databases (rs727504342, gnomAD 0.002%). This missense change has been observed in individual(s) with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 20359594, 21750094, 24749114, 25611685, 27532257, 27600940, 28790153; Invitae). ClinVar contains an entry for this variant (Variation ID: 177826). 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 not expected to disrupt MYH7 protein function with a negative predictive value of 95%. 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. -

Hypertrophic cardiomyopathy 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Apr 10, 2017

This MYH7 Arg1079Gln variant is a rare occurrence in the general population; it is not observed in the 1000 genomes project (http://www.1000genomes.org/), and is a singleton event in the Exome Aggregation Consortium dataset (MAF= 0.000008, http://exac.broadinstitute.org/). We have identified the MYH7 Arg1079Gln variant in an HCM proband where two additional MYBPC3 variants have also been observed in the family (Girolami F, et al., 2010). One of the additional variants (MYBPC3 Gln969Ter) is well described as disease-causing. Segregation analysis showed this MYH7 Arg1079Gln variant to be present in one other affected family member (who also carries the disease causative MYBPC3 Gln969Ter variant). The MYH7 Arg1079Gln has been identified in a general population (Bick AG, et al., 2012) and 2 HCM probands (Alfares AA et al., 2015; Cecconi M et al., 2016), no further evidence is provided in these studies to support a pathogenic role. This variant has also been identified in one DCM patient (WaldmÃ¼ller S, et al., 2011) and double heterozygous amyloidosis with HCM case (Ebrille E, et al., 2013). Predictions from in silico tools are contradictory with SIFT and MutationTaster predicting the amino acid substitution to be "deleterious" and "disease-causing". PolyPhen-2 predicts the impact of this variant to be "benign" (note: no prediction is made by PolyPhen-HCM). Due to limited segregation analysis due to small number of informative individuals, and co-occurrence with a MYBPC3 variant that explains the disease phenotype, we classify this MYH7 Arg1079Gln variant as one of "uncertain significance". -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

CardioboostCm

Benign

0.029

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.56

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.74

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.79

MetaSVM

Benign

-0.41

MutationAssessor

Benign

0.23

MutationTaster

Benign

0.79

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.99

REVEL

Uncertain

0.45

Sift

Benign

0.031

Sift4G

Benign

0.87

Polyphen

0.12

Vest4

0.75

MutPred

0.76

Gain of ubiquitination at K1083 (P = 0.0446);

MVP

0.81

MPC

0.44

ClinPred

0.70

GERP RS

4.9

Varity_R

0.12

gMVP

0.76

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