14-23418234-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM5PP2PP3_ModeratePP5

The NM_000257.4(MYH7):c.4145G>A(p.Arg1382Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000093 in 1,613,394 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. R1382W) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10U:4

Conservation

PhyloP100: 5.93

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 Likely_pathogenic. Variant got 8 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

PM5

Other missense variant is known to change same aminoacid residue: Variant chr14-23418235-G-A 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, 0.933

PP5

Variant 14-23418234-C-T is Pathogenic according to our data. Variant chr14-23418234-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 177788.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=10, Uncertain_significance=3}. Variant chr14-23418234-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4 link	c.4145G>A	p.Arg1382Gln	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.4145G>A	p.Arg1382Gln	missense_variant	Exon 30 of 40	1	NM_000257.4	ENSP00000347507.3		P12883
MIR208B	ENST00000401172.1 link	n.-171G>A		upstream_gene_variant		6

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251460

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000890

AC:

AN:

1461150

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726878

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:10Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Pathogenic:3Uncertain:1

Sep 12, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg1382Gln variant in MYH7 has been identified in at least 15 individuals with HCM (Nunez 2013, Zou 2013, Walsh 2017, Kassem 2017, Ambry pers. comm., Invi tae pers. comm., GeneDx pers. comm., LMM data). It has also been reported by oth er clinical laboratories in ClinVar (Variation ID 177788) and has been identifie d in 1/15304 of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservati on analysis do not provide strong support for or against an impact to the protei n. In summary, although additional studies are required to fully establish its c linical significance, the p.Arg1382Gln variant is likely pathogenic. ACMG/AMP Cr iteria applied: PS4, PM2. -

Dec 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1382 of the MYH7 protein (p.Arg1382Gln). This variant is present in population databases (rs727504325, gnomAD 0.007%). This missense change has been observed in individuals with clinical features of hypertrophic cardiomyopathy (PMID: 23283745, 23782526, 25132132, 27532257, 30972196, 31513939, 31941943, 33673806; internal data). ClinVar contains an entry for this variant (Variation ID: 177788). 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%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Oct 31, 2018

Center for Human Genetics, University of Leuven

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 27, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4145G>A (p.Arg1382Gln) variant in the MYH7 gene has been identified in numerous (>15) affected individuals with Hypertrophic Cardiomyopathy (PMID: 23283745, 23782526, 25132132, 31513939, 33673806, 31941943, 30972196, 28687478, 27532257, 33495597, 30847666, 25611685). In-silico computational prediction tools suggest that this variant may have deleterious effect on the protein function (REVEL score: 0.793). This variant is found to be rare (0.00000397; MAF<0.004%) in the general population database (gnomAD) and interpreted as likely pathogenic by several submitters in the ClinVar database (ClinVar ID: 177788). Another amino acid substitution at the same position, c.4144C>T (p.Arg1382Trp), has been reported in multiple individuals with hypertrophic cardiomyopathy (PMID: 12707239, 24047955, 23283745, 28138913, 27532257). Therefore, the c.4145G>A (p.Arg1382Gln) variant in the MYH7 gene is classified as likely pathogenic. -

not provided

Pathogenic:2Uncertain:2

Aug 03, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 15, 2018

Blueprint Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 21, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22958901, 27247418, 23782526, 23283745, 27532257, 24047955, 30972196, 31513939, 25132132, 28687478, 31941943, 31447099, 33673806, 28606303, Li_2024_Article, 37652022, 37937776) -

Jan 21, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy

Pathogenic:2

Apr 05, 2023

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 13, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with glutamine at codon 1382 in the LMM domain of the MYH7 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 20 individuals affected with hypertrophic cardiomyopathy (PMID: 23283745, 27532257, 28687478, 30972196, 31941943, 33495597, 33673806, Kassem 2017, Luo et al., 2019; communication with an external laboratory; ClinVar Variation ID: 177788). This variant has been identified in 1/251460 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Dilated cardiomyopathy 1S;C1842160:Myosin storage myopathy;C1850709:Myopathy, myosin storage, autosomal recessive;C3495498:Hypertrophic cardiomyopathy 1;C4552004:MYH7-related skeletal myopathy

Pathogenic:1

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PS4+PP3_Moderate -

not specified

Pathogenic:1

Sep 27, 2022

Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Pathogenic:1

May 15, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4145G>A (p.R1382Q) alteration is located in exon 30 (coding exon 28) of the MYH7 gene. This alteration results from a G to A substitution at nucleotide position 4145, causing the arginine (R) at amino acid position 1382 to be replaced by a glutamine (Q). Based on data from gnomAD, the A allele has an overall frequency of <0.001% (1/251460) total alleles studied. The highest observed frequency was 0.006% (1/16256) of African alleles. This variant has been detected in numerous individuals with hypertrophic cardiomyopathy (HCM) (Núñez, 2013; Zou, 2013; Kassem, 2017; Walsh, 2017; García-Molina, 2019; Ambry internal data; external communication). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

MYH7-related disorder

Uncertain:1

Dec 19, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MYH7 c.4145G>A variant is predicted to result in the amino acid substitution p.Arg1382Gln. This variant has been reported in the heterozygous state in ten individuals with hypertrophic cardiomyopathy (HCM) (Nunez et al. 2013. PubMed ID: 23782526; Zou et al. 2013. PubMed ID: 23283745; Table S1B, Walsh et al. 2017. PubMed ID: 27532257; García-Molina et al. 2019. PubMed ID: 30972196; Table S2, Robyns et al. 2020. PubMed ID: 31513939; Additional File 2, Hathaway et al. 2021. PubMed ID: 33673806). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. In an updated version of the gnomAD this variant is reported in 0.036% of alleles in individuals of Middle Eastern descent (https://gnomad.broadinstitute.org/variant/14-23418234-C-T?dataset=gnomad_r4) which may be too common to be a cause of disease (Kelly et al. 2018. PubMed ID: 29300372). In ClinVar, this variant has conflicting interpretations of pathogenicity, ranging from uncertain to likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/177788/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

CardioboostCm

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.82

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.93

MetaSVM

Uncertain

0.70

MutationAssessor

Pathogenic

3.6

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-3.0

REVEL

Pathogenic

0.79

Sift

Uncertain

0.0010

Sift4G

Benign

0.13

Polyphen

1.0

Vest4

0.93

MutPred

0.63

Loss of MoRF binding (P = 0.0583);

MVP

0.99

MPC

1.7

ClinPred

1.0

GERP RS

4.8

Varity_R

0.72

gMVP

0.89

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