chr14-23433131-C-T

Position:

chr14-23433131-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP2PP3_Moderate

The NM_000257.4(MYH7):c.298G>A(p.Ala100Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,614,118 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 (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:5

Conservation

PhyloP100: 2.58

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 3 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, 0.925

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH7	NM_000257.4 linkuse as main transcript	c.298G>A	p.Ala100Thr	missense_variant	4/40	ENST00000355349.4	NP_000248.2	P12883
MYH7	NM_001407004.1 linkuse as main transcript	c.298G>A	p.Ala100Thr	missense_variant	3/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.298G>A	p.Ala100Thr	missense_variant	4/40	1	NM_000257.4	ENSP00000347507.3		P12883

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152108

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251476

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135914

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000233

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000289

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:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000252

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

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

Alfa

AF:

0.0000278

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 17, 2023	This missense variant replaces alanine with threonine at codon 100 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 an individual affected with dilated cardiomyopathy (PMID: 26084686). It has also been reported in two unrelated individuals affected with hypertrophic cardiomyopathy who both carried additional pathogenic variants (PMID: 22765922, 23396983, 23870641, 25351510, 26654849, 27532257, 28356264). This variant has been identified in 4/251476 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	Aug 03, 2023	This missense variant replaces alanine with threonine at codon 100 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 an individual affected with dilated cardiomyopathy (PMID: 26084686). It has also been reported in two unrelated individuals affected with hypertrophic cardiomyopathy who both carried additional pathogenic variants (PMID: 22765922, 23396983, 23870641, 25351510, 26654849, 27532257, 28356264). This variant has been identified in 4/251476 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. -

Restrictive cardiomyopathy

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Blueprint Genetics

Jul 03, 2014

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 20, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 HCM proband (PMID 22765922), 1 Finnish DCM proband (PMID 26084686); No segregation data; ClinVar: LP by Blueprint -

Hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 12, 2022

ClinVar contains an entry for this variant (Variation ID: 180430). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 22765922, 27532257). This variant is present in population databases (rs730880154, gnomAD 0.003%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 100 of the MYH7 protein (p.Ala100Thr). -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 21, 2023

The p.A100T variant (also known as c.298G>A), located in coding exon 2 of the MYH7 gene, results from a G to A substitution at nucleotide position 298. The alanine at codon 100 is replaced by threonine, an amino acid with similar properties. This variant has been detected in hypertrophic cardiomyopathy cohorts; however, case reports may overlap and some individuals also had mutations other cardiomyopathy-related genes (Coto E et al. J Mol Diagn, 2012 Sep;14:518-24; Reguero JR et al. Int J Cardiol, 2013 Oct;168:4555-6; Lopes LR et al. J Med Genet, 2013 Apr;50:228-39; Lopes LR et al. Heart, 2015 Feb;101:294-301; Gómez J et al. Rev Esp Cardiol (Engl Ed), 2016 Jan;69:61-8; Walsh R et al. Genet Med, 2017 02;19:192-203). This variant has also been detected in an individual from a dilated cardiomyopathy cohort; however, details were limited (Akinrinade O et al. Eur Heart J, 2015 Sep;36:2327-37). This alteration was also noted in a biobank cohort (Park J et al. Hum Mol Genet, 2022 Mar;31:827-837). This amino acid position is well 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

Pathogenic

0.82

CardioboostCm

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

Eigen

Uncertain

0.21

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.91

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.93

MetaSVM

Uncertain

0.44

MutationAssessor

Benign

0.70

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-1.7

REVEL

Pathogenic

0.69

Sift

Uncertain

0.013

Sift4G

Uncertain

0.026

Polyphen

0.95

Vest4

0.88

MVP

0.90

MPC

2.1

ClinPred

0.76

GERP RS

3.8

Varity_R

0.42

gMVP

0.83

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