rs876657887

Positions:

• chr14-23431640-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2_Supporting PS4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.677C>T (p.Ala226Val) variant in MYH7 has been identified in at least 7 individuals with HCM (PS4_Moderate; Homburger 2016 PMID:27247418; Walsh 2017 PMID:27532257; Ho 2018 PMID:30297972; Toepfer 2020 PMID:31983222; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.). This variant was absent from large population studies (PM2_Supporting; http://gnomad.broadinstitute.org, v2.1.1). Following the ClinGen Sequence Variant Interpretation (SVI) working group recommendation for weight adjustment of the PM2 criterion due to concerns that rarity in the general population may not meet the relative odds of pathogenicity for moderate evidence, the PM2 criterion was downgraded to PM2_Supporting. This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, due to insufficient evidence, this variant meets criteria to be classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate; PM2_Supporting; PM1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10576963/MONDO:0005045/002

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 1.52

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.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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.677C>T	p.Ala226Val	missense_variant	8/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.677C>T	p.Ala226Val	missense_variant	7/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.677C>T	p.Ala226Val	missense_variant	8/40	1	NM_000257.4	ENSP00000347507.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 16, 2023

ClinVar contains an entry for this variant (Variation ID: 228918). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 27247418, 27532257; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 226 of the MYH7 protein (p.Ala226Val). For these reasons, this variant has been classified as Pathogenic. This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 15, 2024

The p.A226V variant (also known as c.677C>T), located in coding exon 6 of the MYH7 gene, results from a C to T substitution at nucleotide position 677. The alanine at codon 226 is replaced by valine, an amino acid with similar properties. This alteration has been detected in several individuals reported to have hypertrophic cardiomyopathy (HCM) (Walsh R et al. Genet. Med., 2017 02;19:192-203; Ho CY et al. Circulation, 2018 Oct;138:1387-1398; Ambry internal data; external communication). This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). Another alteration at the same codon, p.A226T (c.676G>A), has been described in association with HCM (Bottillo I et al. Gene. 2016;577:227-35). This variant is also considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 21, 2015

The p.Ala226Val variant in MYH7 has not been previously reported in individuals with cardiomyopathy or in large population studies. Computational prediction too ls and conservation analysis do not provide strong support for or against an imp act to the protein. In summary, the clinical significance of the p.Ala226Val var iant is uncertain. -

Hypertrophic cardiomyopathy 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Mar 31, 2022

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established, however, missense variants have been proposed to act in a dominant negative manner (PMID: 24714796). (I) 0108 - This gene is associated with both recessive and dominant disease. Pathogenic variants in this gene are usually heterozygous, however a recessive inheritance pattern has been observed in severe cases (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 29300372). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0252 - This variant is homozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. This variant is found within the head region, which is enriched with pathogenic missense variants (PMID: 29300372). (SP) 0708 - Another missense variant comparable to the one identified in this case has conflicting previous evidence for pathogenicity. The p.(Ala226Thr) variant has been classified mainly as VUS and likely pathogenic by clinical diagnostic laboratories. Additionally, based on in silico prediction tools, this variant has also been reported as likely pathogenic and VUS in an Italian study of hypertrophic cardiomyopathy (ClinVar, PMIDs: 27600940, 27483260). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported in individuals with hypertrophic cardiomyopathy (HCM) and classified as VUS, likely pathogenic or pathogenic by clinical diagnostic laboratories and in the literature (ClinVar, PMIDs: 27247418, 31568572, 33495597). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1001 - This variant has strong functional evidence supporting abnormal protein function. Myosin ATP binding assays performed on human cardiac ventricular tissues from a HCM patient heterozygous for this variant demonstrated altered interacting-heads motif residues. Additionally, reduced proportions of myosin and myosin heads in the super-relaxed head conformation, and increased proportions of myosin and myosin heads in the disordered-relaxed state conformation compared to WT healthy tissues were observed (PMID: 31983222). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
CardioboostCm	Uncertain	0.83
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.33	N
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.022	D
MutationAssessor	Benign	-0.19	N
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.69	N
REVEL	Uncertain	0.44
Sift	Benign	0.099	T
Sift4G	Benign	0.59	T
Polyphen		0.87	P
Vest4		0.76
MutPred		0.36		Gain of catalytic residue at N224 (P = 0.0885);
MVP		0.97
MPC		2.1
ClinPred		0.44	T
GERP RS		3.3
Varity_R		0.18
gMVP		0.87

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: rs876657887; hg19: chr14-23900849;