14-23415832-C-A

Position:

chr14-23415832-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP2PP3_Strong

The NM_000257.4(MYH7):c.4954G>T(p.Asp1652Tyr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000039 in 1,614,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense, splice_region

Scores

Splicing: ADA: 0.9999

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:12

Conservation

PhyloP100: 7.37

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:

MHRT (HGNC:):

MHRT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 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, 0.964

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH7	NM_000257.4 linkuse as main transcript	c.4954G>T	p.Asp1652Tyr	missense_variant, splice_region_variant	35/40	ENST00000355349.4	NP_000248.2	P12883
MYH7	NM_001407004.1 linkuse as main transcript	c.4954G>T	p.Asp1652Tyr	missense_variant, splice_region_variant	34/39		NP_001393933.1
MHRT	NR_126491.1 linkuse as main transcript	n.261+3C>A		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.4954G>T	p.Asp1652Tyr	missense_variant, splice_region_variant	35/40	1	NM_000257.4	ENSP00000347507.3		P12883

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.000478

GnomAD3 exomes

AF:

0.0000477

AC:

AN:

251342

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135856

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

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:

0.0000528

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000397

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000157

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:

0.0000432

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

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:

0.000478

Alfa

AF:

0.0000980

Hom.:

Bravo

AF:

0.0000869

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2024	Reported in association with different cardiomyopathy presentations (DCM, HCM and restrictive cardiomyopathy) (PMID: 19659763, 21302287, 27247418, 27532257, 28356264, 28408708, 32894683 ); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 33588347, 27532257, 26633542, 27247418, 21302287, 28790153, 28356264, 33495597, 32894683, 19659763, 32528171, 34542152, 36243179, 36129056, 35537032, 28408708, 33495596, 37652022) -
Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jul 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 26, 2021	- -

Cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 09, 2023	This missense variant replaces aspartic acid with tyrosine at codon 1652 of the MYH7 protein. Computational prediction suggests that this variant may have a 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 individuals affected with hypertrophic cardiomyopathy (PMID: 19659763, 21302287, 27247418, 27532257, 28356264, 28790153, 33588347, 33495596, 33495597). This variant has also been identified in 12/251342 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	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 16, 2023	- -

Hypertrophic cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 05, 2019	Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in one proband with HCM (Burns 2017), one proband with HCM with a family history of sudden death (Roncarati 2011), and one 13 yr old with HCM whose father and sister with RCM and DCM also had the variant (Frisso 2009). Predicted pathogenic. Gnomad: 0.01%. Clinvar: VUS (GeneDx, Agnes Ginges, LMM), LP (Invitae). -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 1652 of the MYH7 protein (p.Asp1652Tyr). This variant is present in population databases (rs397516233, gnomAD 0.01%). This missense change has been observed in individuals with clinical features of hypertrophic cardiomyopathy or limb-girdle weakness (PMID: 19659763, 21302287, 27247418, 27532257, 28356264, 28790153, 32528171). ClinVar contains an entry for this variant (Variation ID: 43047). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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:2

Uncertain significance, criteria provided, single submitter	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Mar 09, 2017	This MYH7 Asp1652Tyr variant has been described in two Italian HCM patients (Frisso G, et al., 2009; Roncarati R, et al., 2011). Segregation analysis provided by Frisso G et al. (2009) identified two family members who also carry this variant. Both members however, did not have typical HCM characteristics but rather a dilated (proband's sister) and restrictive (proband's father) cardiomyopathy phenotype. We have identified this MYH7 Asp1652Tyr variant in an isolated HCM patient of North West European descent. Clinical screening of the family revealed no family history of HCM and/or sudden cardiac death. We note that additional uncertain variants have been identified in the proband which may contribute to the disease phenotype (MYL2 Ala13Thr; DSG2 Asp535Glu). The MYH7 Asp1652Tyr variant is absent in 1000 genomes project (http://www.1000genomes.org/), and has a frequency of 0.00002475 in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). Aspartic acid at position 1652 is highly conserved across distantly related species, and computational tools predict the Asp1652Tyr to be "deleterious" (SIFT) and "disease-causing" (MutationTaster). Additionally, Polyphen_HCM (Jordan DM, et al., 2011) predicts that this MYH7 Asp1652Tyr variant is causative of the disease. Based on this information, we classify MYH7 Asp1652Tyr as a variant of "uncertain significance". -
Uncertain significance, criteria provided, single submitter	clinical testing	Servicio Canario de Salud, Hospital Universitario Nuestra Sra. de Candelaria	Sep 23, 2021	The c.4954G>T (p.Asp1652Tyr) MYH7 variant has been reported in our laboratory in a 44-year-old patient with diagnosis of hypertrophic cardiomyopathy. Mother (with permanent atrial fibrillation and pacemaker) and maternal grandmother with the same diagnosis. This variant is present in population databases (gnomAD allele frequency 0.00004774, 12/251342 alleles) being more frequent in the Latino population (gnomAD allele frequency 0.0001446). This variant has been previously reported in a patients with hypertrophic cardiomyopathy [PMID 28790153, 27247418, 27532257, 28356264]. ClinVar contains an entry for this variant (Variation ID: 43047). In silico analysis (CADD, Mutation Taster, SIFT, Provean, PolyPhen2) supports that this missense variant has a deleterious effect on protein structure/function. Some in silico splicing studies predict that it affects the natural splicing acceptor of intron 34, but there are no in vitro or in vivo functional studies, as well as RNA studies that have verified this aspect. In summary, c.4954G>T (p.Asp1652Tyr) MYH7 variant is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Sep 12, 2024

Variant summary: MYH7 c.4954G>T (p.Asp1652Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a 3' acceptor site. One predict the variant no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.8e-05 in 252126 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MYH7 causing Hypertrophic Cardiomyopathy (4.8e-05 vs 0.001), allowing no conclusion about variant significance. c.4954G>T has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy (Frisso_2009, Roncarati_2011, Gomez_2017, Homburger_2016, Mori_2021). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 19659763, 21302287, 28356264, 27247418, 33588347). ClinVar contains an entry for this variant (Variation ID: 43047). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Congenital myopathy with fiber type disproportion;C1834481:Dilated cardiomyopathy 1S;C1842160:Myosin storage myopathy;C1850709:Myopathy, myosin storage, autosomal recessive;C3495498:Hypertrophic cardiomyopathy 1;C4552004:MYH7-related skeletal myopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 05, 2021

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 16, 2024

The p.D1652Y variant (also known as c.4954G>T) is located in coding exon 33 of the MYH7 gene. The aspartic acid at codon 1652 is replaced by tyrosine, an amino acid with highly dissimilar properties. This change occurs in the first base pair of coding exon 33. This variant has been detected in cohorts with hypertrophic cardiomyopathy and neuromuscular phenotypes (Frisso G et al. Clin Genet, 2009 Jul;76:91-101; Roncarati R et al. J Cell Physiol, 2011 Nov;226:2894-900; Homburger JR et al. Proc Natl Acad Sci U S A, 2016 Jun;113:6701-6; Gómez J et al. Circ Cardiovasc Genet, 2017 Apr;10; Ingles J et al. Circ Cardiovasc Genet, 2017 Apr;10; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Töpf A et al. Genet Med, 2020 Sep;22:1478-1488). 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

Pathogenic

0.65

CardioboostCm

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.89

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.84

MetaRNN

Pathogenic

0.96

MetaSVM

Pathogenic

0.87

MutationAssessor

Pathogenic

4.0

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-4.8

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.82

MVP

0.99

MPC

1.7

ClinPred

0.97

GERP RS

5.3

Varity_R

0.83

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.99

SpliceAI score (max)

0.25

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.25

Position offset: -9

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