chr14-23418244-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PP2PP3_ModeratePP5_Very_Strong

The NM_000257.4(MYH7):c.4135G>A(p.Ala1379Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,613,426 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 5.90

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:

MIR208B (HGNC:33669): (microRNA 208b) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

MIR208B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM1

In a helix (size 64) in uniprot entity MYH7_HUMAN there are 16 pathogenic changes around while only 1 benign (94%) in NM_000257.4

PM2

Very rare variant in population databases, with high coverage;

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, 0.922

PP5

Variant 14-23418244-C-T is Pathogenic according to our data. Variant chr14-23418244-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23418244-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4 link	c.4135G>A	p.Ala1379Thr	missense_variant	Exon 30 of 40	ENST00000355349.4	NP_000248.2	P12883

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4 link	c.4135G>A	p.Ala1379Thr	missense_variant	Exon 30 of 40	1	NM_000257.4	ENSP00000347507.3		P12883
MIR208B	ENST00000401172.1 link	n.-181G>A		upstream_gene_variant		6

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461214

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726914

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74364

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

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Pathogenic:3

Feb 07, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ala1379Thr variant in MYH7 has been reported in >10 families with HCM and segregated with disease in >15 affected relatives (Blair 2002, Richard 2003, Zou 2013, Burns 2016, Walsh 2017, LMM data). It has also been identified in 1/35440 Latino chromosomes in gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID 42993). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner. ACMG/AMP criteria applied: PS4, PP1_Strong, PM2_Supporting, PP3. -

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1379 of the MYH7 protein (p.Ala1379Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 11861413, 12707239, 23283745, 27247418, 27532257, 28790153). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42993). 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. -

Sep 27, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4135G>A (p.Ala1379Thr) variant in MYH7 gene, that encodes for myosin heavy chain 7, has been identified in multiple unrelated individuals (>18) affected with hypertrophic cardiomyopathy (HCM) and segregated with disease in 15 individuals in three unrelated families (PMID: 28790153, 12707239, 23283745, 27532257,11861413). Computational prediction tools suggest that the p.Ala1379Thr variant may have deleterious effect on the protein function (REVEL score: 0.773). This variant is rare (3/1613426 chromosomes; 0.0001859%) in the general population database, gnomAD (v4.1.0) and interpreted as likely pathogenic/pathogenic by multiple submitters in the ClinVar database (ID: 42993). Therefore, the c.4135G>A (p.Ala1379Thr) variant in the MYH7 gene is classified as pathogenic. -

Hypertrophic cardiomyopathy 1

Pathogenic:3

Dec 11, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PP1_STR,PS4_MOD,PM5,PM2_SUP,PP3 -

Aug 23, 2018

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

MYH7 Ala1379Thr has previously been identified in multple HCM cases (Walsh R et al., 2017; Zou Y et al., 2013; Richard P et al., 2003; Blair E et al., 2002). Familial analysis by Blair E. et al. (2002) demonstrated strong segregation of this variant with disease phenotype. We have detected this variant in 4 unrelated HCM families, 3 of which were reported previously (Ingles J et al., 2017; Burns et al., 2017) and segregated to an additional 3 affected family members in one family. Furthermore, this variant is absent in both the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/) and 1000 genomes project (http://www.1000genomes.org/). In silico tools SIFT, MutationTaster and PolyPhen-2 predict that the variant is deleterious. More specifically, a tool designed to predict the effects of missense variants in HCM genes (Jordan DM, et al., 2011), predicts this MYH7 Ala1379Thr variant to be "Pathogenic". Based on the adapted ACMG guidelines (Kelly MA, et al., 2018), this variant has been identified in more than 10 unrelated probands (PS4_Strong), has strong segregation data (PP1_Strong), is rare in the general population (PM2) and in silico tools predict that it is deleterious (PP3), therefore we classify MYH7 Ala1379Thr as 'pathogenic'. -

Feb 18, 2016

Center for Medical Genetics Ghent, University of Ghent

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:2

Jul 13, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 19, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25961035, 28166811, 30466861, 23283745, 16918501, 11861410, 22199023, 21310275, 12707239, 27532257, 27247418, 28790153, 28615295, 33631351, 33673806, 32894683, 33087929, 36252119, 36264615, 37498360, 37652022, 36243179, 35935646, 34076677, 15136674, 12951062, 37079208, 11861413) -

Primary familial hypertrophic cardiomyopathy

Pathogenic:2

Oct 16, 2013

Blueprint Genetics

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 27, 2020

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MYH7 c.4135G>A (p.Ala1379Thr) 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 was absent in 251464 control chromosomes (gnomAD). c.4135G>A has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (Richard_2003, Blair_2002, Ross_2017). Blair_2002 reported that this variant segregated with disease in three unrelated families and was not present in 200 control chromosomes. These data indicate that the variant is very likely to be associated with disease. At least one publication, Flashman_2007, reports this variant has no effect on interaction with C10 of cMyBP-C. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (3x) and likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic. -

Cardiomyopathy

Pathogenic:1

Aug 20, 2021

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Pathogenic:1

Jan 25, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A1379T pathogenic mutation (also known as c.4135G>A), located in coding exon 28 of the MYH7 gene, results from a G to A substitution at nucleotide position 4135. The alanine at codon 1379 is replaced by threonine, an amino acid with some similar properties. This variant was reported to segregate with hypertrophic cardiomyopathy (HCM) or related features in multiple individuals across three HCM proband-identified families, and has also been detected in additional HCM cohorts (Blair E et al. Circ Res. 2002;90:263-9; Zou Y et al. Mol Biol Rep. 2013;40:3969-76; Richard P et al. Circulation. 2003;107:2227-32; Walsh R et al. Genet. Med., 2017 Feb;19:192-203). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

CardioboostCm

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.82

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

M_CAP

Pathogenic

0.86

MetaRNN

Pathogenic

0.92

MetaSVM

Uncertain

0.43

MutationAssessor

Uncertain

2.8

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-2.7

REVEL

Pathogenic

0.77

Sift

Benign

0.068

Sift4G

Uncertain

0.030

Polyphen

1.0

Vest4

0.85

MutPred

0.51

Gain of phosphorylation at A1379 (P = 0.0206);

MVP

0.95

MPC

1.3

ClinPred

0.98

GERP RS

4.8

Varity_R

0.25

gMVP

0.91

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