rs730880817

Positions:

• chr14-23415155-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PS4_Supporting PP1_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000257.4(MYH7):c.5399C>T (p.Ala1800Val) variant has been identified in 2 individuals with DCM (PS4_Supporting; GeneDx pers. comm.; LMM pers. comm.) and segregated with DCM in 6 affected relatives from 1 family (PP1_Moderate; GeneDx pers. comm.). This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis did not provide evidence for or against an impact to the protein. In summary, due to insufficient evidence, this variant is classified as uncertain significance for dilated cardiomyopathy (DCM) in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting, PP1_Moderate, PM2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA016070/MONDO:0005021/002

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 9.82

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH7	NM_000257.4	c.5399C>T	p.Ala1800Val	missense_variant	37/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.5399C>T	p.Ala1800Val	missense_variant	36/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.5399C>T	p.Ala1800Val	missense_variant	37/40	1	NM_000257.4	ENSP00000347507.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Nov 16, 2012	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. We classify it as likely disease causing, and suitable for predictive testing of at-risk family members. This is a novel variant. This is a conservative amino acid change. The Alanine at position 1800 is conserved throughout evolution. Other variants have been reported in association with disease at nearby codons according to HGMD: p.Asp1792Gly (Waldmuller et al 2011; associated with dilated cardiomyopathy), p.Leu1793Pro (Dye et al 2006, Uro-Coste et al 2009; reported in a case of myosin storage myopathy), p.Gln1794Glu (Lakdawala et al 2012; dilated cardiomyopathy); Glu1801Gly (Waldmuller et al. 2011; dilated cardiomyopathy), p.Gly1808Ser (Marsiglia et al 2013; hypertrophic cardiomyopathy), and p.Gly1808Ala (Hershberger et al 2008; dilated cardiomypathy). In silico analysis with PolyPhen2 predicts the variant to be probably damaging. In total this variant has apparently been seen in at least 4 individuals in this family with some sort of cardiomyopathy phenotype including Elijah, his mother (an obligate carrier), his grandfather, and the half-uncle who had a cardiac arrest at the age of seven. Thus we have moderate segregation data in this family. The variant has not been seen in >6700 individuals including GeneDx controls and individuals from population databases. GeneDx did not see this variant in a sample of 289 control individuals of different ethnic backgrounds (unclear how many match the patient’s African American ancestry). The variant is not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~6500 Caucasian and African American individuals (as of January, 2014). About 2200 individuals match the patient’s ancestry. The variant is not listed in 1000 Genomes. Based on these data we would consider this variant likely disease causing. The segregation data and absence in >2200 ancestry-matched individuals does support pathogenicity. Further segregation data in the patient's other affected relatives could strengthen confidence in the pathogenicity. The patient’s mother reports that some of her other affected half-sibs have already been tested but we don't have that data. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 30, 2021	Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar (ClinVar Variant ID#181279; Landrum et al., 2016) -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 28, 2015

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Ala1800Va l variant in MYH7 has not been previously reported in individuals with cardiomyo pathy or in large population studies. Alanine (Ala) at position 1800 is highly c onserved in evolution and the change to valine (Val) was predicted to be pathoge nic using a computational tool clinically validated by our laboratory. This tool 's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011 ). In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Ala1800Val variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
CardioboostCm	Benign	0.032
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Uncertain	2.5	M
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.020	D
Sift4G	Benign	0.14	T
Polyphen		1.0	D
Vest4		0.75
MutPred		0.37		Gain of catalytic residue at L1797 (P = 0.0916);
MVP		0.99
MPC		1.5
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.42
gMVP		0.97

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

Other links and lift over

dbSNP: rs730880817; hg19: chr14-23884364;