rs397516225

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PP5_Strong

The NM_000257.4(MYH7):c.4588C>T(p.Arg1530Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,614,062 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 (★★★). Synonymous variant affecting the same amino acid position (i.e. R1530R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

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

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

MYH7
NM_000257.4 stop_gained

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:2U:6

Conservation

PhyloP100: 0.889

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 Pathogenic. Variant got 12 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 14-23416924-G-A is Pathogenic according to our data. Variant chr14-23416924-G-A is described in ClinVar as [Uncertain_significance]. Clinvar id is 43029.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=5, Likely_pathogenic=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MYH7	NM_000257.4 linkuse as main transcript	c.4588C>T	p.Arg1530Ter	stop_gained	33/40	ENST00000355349.4
MHRT	NR_126491.1 linkuse as main transcript	n.567G>A		non_coding_transcript_exon_variant	4/6
MYH7	NM_001407004.1 linkuse as main transcript	c.4588C>T	p.Arg1530Ter	stop_gained	32/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.4588C>T	p.Arg1530Ter	stop_gained	33/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251416

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135882

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:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000629

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2Uncertain:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cardiomyopathy

Pathogenic:1Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 20, 2018	The p.Arg1530X variant in MYH7 has been identified by our laboratory in trans wi th a likely pathogenic MYH7 missense variant in 2 Caucasian individuals with chi ldhood-onset DCM from 1 family. This variant has also been identified in 4/24619 0 chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadins titute.org; rs397516255). This nonsense variant leads to a premature termination codon at position 1530, which is predicted to lead to a truncated or absent pro tein. It should be noted that LOF variants in the MYH7 gene are very rare and th eir phenotypic consequences are not yet well-defined. Although heterozygous loss -of-function (LOF) variants in MYH7, such as this variant, are not believed to b e pathogenic for dominant forms of cardiomyopathy (this variant was classified a s a variant of uncertain significance in the context of autosomal dominant cardi omyopathy by the ClinGen-approved Inherited Cardiomyopathy expert panel (ClinVar SCV000564453.2), there is evidence that can they lead to severe and early onset disease when present in trans with a second MYH7 variant (LMM data). In summary , although additional studies are required to fully establish its clinical signi ficance, the p.Arg1530X variant is likely pathogenic for cardiomyopathy in an au tosomal recessive manner. ACMG/AMP Criteria applied: PVS1_Moderate; PM2; PM3. -
Uncertain significance, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Mar 22, 2021	The c.4588C>T (p.Arg1530Ter) variant in MYH7 has been identified in 1 individual with DCM who also carried another MYH7 missense variant, and both variants were also identified in the individual's affected sibling (DCM). This nonsense variant was inherited from their unaffected father and the p.Arg143Trp variant was inherited from their unaffected mother (Hershkovitz 2019 PMID:30588760; Partners LMM ClinVar SCV000059574.5). This variant has also been identified in 2 individuals with myopathy (Invitae ClinVar SCV000749836.2; pers. comm.) and 1 adolescent with RCM, who inherited the MYH7 variant from his unaffected father, and was also found to have a de novo truncating TNNI3 variant (Ambry Genetics ClinVar SCV000318079.4; pers. comm.). PS4_Supporting was not applied due to the variability in proband phenotypes and occurrence of additional variants. This variant has been identified in 0.0003% (FAF 95% CI, 2/113694) of European chromosomes in gnomAD v2.1.1 (PM2; http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 1530 leading to a truncated or absent protein. The contribution of LOF variants in MYH7 to autosomal dominant inherited cardiomyopathy is incompletely understood. In summary, due to insufficient evidence, this variant is classified as uncertain significance for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM2. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 07, 2023	This variant changes 1 nucleotide in exon 33 of the MYH7 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with childhood-onset dilated cardiomyopathy, who also carried a pathogenic p.Arg143Trp variant in the same gene that could explain the observed phenotype (PMID: 30588760). This variant has also been reported in two individuals affected with left ventricular noncompaction (PMID: 30471092, 33500567). This variant has been identified in 4/251416 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Clinical relevance of loss-of-function MYH7 truncation variants in autosomal dominant cardiovascular disorders is not clearly established. 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. -

MYH7-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Jan 01, 2019

- -

not specified

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Apr 08, 2015

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Arg1530Stop (R1530X; c.4588 C>T) in the MYH7 gene We classify it as a Variant of Unknown Significance (VUS). Particular caution is warranted in interpreting this truncating variant in MYH7, because a loss of function mutation in MYH7 as a mechanism for cardiopathology has not been well described. However, it is not clear that premature stop codons in the gene MYH7 typically cause disease. According to the lab, of the 410 total MYH7 alterations reported in the Human Gene Mutation Database (HGMD), only 7 are nonsense alterations leading to a premature stop codon. Furthermore, two studies in the literature show MYH7 truncating mutations failing to segregate with disease. In one study, MYH7-p.Q1334X was thought not to be disease-causing but to increase the severity of disease when a second MYH7 mutation was present. It was identified in trans with a missense MYH7 mutation in one individual with hypertrophic cardiomyopathy (HCM) and was also carried by the individual's healthy mother. The missense mutation was carried by the mildly-affected father. Likewise, the individual's affected sister carried the missense mutation but did not carry MYH7-p.Q1334X (Hougs et al. 2005 Eur J Hum Genet 13(2):161-5). In another study, MYH7-p.R54X was detected in a patient with HCM, but it did not segregate with disease in the family (Nishi et al. 1995 Circulation 91:2911-2915). In yet another study, such a variant did segregate with disease but not alone: The MYH7-p.E1455X was detected in trans with a missense MYH7 alteration and with a missense MYBPC3 alteration in a patient with HCM. The missense variants in MYH7 and MYBPC3 were detected in isolation in two unaffected individuals in this family, while the MYH7-p.E1455X variant was detected with the MYBPC3 missense variant in two other affected individuals (Girolami et al. 2010 JACC 55(14):1444-53). The p.Arg1530Stop variant was not present in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. However, there are two other premature stop variants present in the NHLBI ESP. One is a nonsense variant that has been seen in 1/4403 African American alleles. The other is a frameshift that occurred in 2/4264 African American alleles. 1000 Genomes also contains two stop gained mutations for MYH7, with dbSNP as the source: rs45620235 (E1669X) and rs141735183 (E1117X), and lists 3 frameshift variants: rs35187609, rs34856803, rs35765584. -

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

Jan 06, 2022

- -

Hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 25, 2023

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. ClinVar contains an entry for this variant (Variation ID: 43029). This premature translational stop signal has been observed in individual(s) with clinical features of MYH7-related conditions (PMID: 30471092, 30588760, 33500567). This variant is present in population databases (rs397516225, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Arg1530*) in the MYH7 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in MYH7 cause disease. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 22, 2022

The p.R1530* variant (also known as c.4588C>T) located in coding exon 31 of the MYH7 gene results from a C to T substitution at nucleotide position 4588. This changes the amino acid from an arginine to a stop codon within coding exon 31. This variant co-occurred in trans with an MYH7 missense variant in two sibling with pediatric-onset severe dilated cardiomyopathy whose parents each carried one variant and were unaffected while a third child with only p.R1530* was also unaffected at the time of study (Hershkovitz T et al. Am J Med Genet A. 2019 Mar;179(3):365-372). This variant has been detected in individuals from left ventricular noncompaction cohorts (Richard P et al. Clin Genet. 2019 Mar;95(3):356-367; Mazzarotto F. Genet Med. 2021 May;23(5):856-864). This variant has also been detected in exome sequencing cohorts and biobank participants; however, clinical details were limited (Park J et al. Hum Mol Genet. 2022 Mar;31(5):827-837; Yang Q et al. J Am Heart Assoc. 2022 Oct;11(19):e025257). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, loss of function of MYH7 has not been clearly established as a mechanism of disease. 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

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.62

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Benign

0.40

MutationTaster

Benign

1.0

Vest4

0.95

GERP RS

4.9

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