rs727503271

chr14-23429901-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_000257.4(MYH7):c.1012G>A(p.Val338Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V338A) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 0.647

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 Pathogenic. Variant got 17 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_000257.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-23429900-A-G is described in ClinVar as [Uncertain_significance]. Clinvar id is 42818.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.
• PP2: Missense variant where missense usually causes diseases, MYH7
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.884
• PP5: Variant 14-23429901-C-T is Pathogenic according to our data. Variant chr14-23429901-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 164381.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr14-23429901-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4	c.1012G>A	p.Val338Met	missense_variant	12/40	ENST00000355349.4
MYH7	NM_001407004.1	c.1012G>A	p.Val338Met	missense_variant	11/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4	c.1012G>A	p.Val338Met	missense_variant	12/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:3

Likely pathogenic, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Sep 27, 2021	The NM_000257.4(MYH7):c.1012G>A (p.Val338Met) variant in MYH7 has been identified in at least 11 individuals with HCM (PS4_Moderate; Homburger 2016 PMID:27247418; Walsh 2017 PMID:27532257; Ambry, pers. comm.; Centenary Institute Sydney pers. comm.; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.), and at least in a presumably unaffected individual (<40 years old) with a family history of HCM (Valente 2013 PMID: 23690394; Captur 2014 PMID:25228707). This variant segregated with disease in 6 affected relatives with HCM from 3 families (PP1_Moderate, GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.). This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). 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 associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate, PP1_Moderate; PM2, PM1. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 338 of the MYH7 protein (p.Val338Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 23690394, 27247418, 27532257, 32746448; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 164381). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 20, 2014	The p.Val338Met variant in MYH7 has been identified by our laboratory in 2 indiv iduals with HCM and segregated with disease in 5 affected relatives from 1 famil y. Of note, affected individuals are reported to have varying ages of onset (age 3 - 50's). This variant was also identified in 2 teenagers with early signs of left ventricular wall thickening and in 3 asymptomatic obligate carriers. This v ariant was absent from large population studies. Computational prediction tools and conservation analyses do not provide strong evidence for or against an impac t to the protein. In summary, although additional studies are required to fully establish its clinical significance, the p.Val338Met variant is likely pathogeni c. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 09, 2018	The V338M likely pathogenic variant in the MYH7 gene has been reported in association with cardiomyopathy (Valente et al., 2013; Captur et al., 2014; Walsh et al., 2017). This variant has also been classified as a likely pathogenic variant and reported to segregate with disease in multiple members from one family by another clinical laboratory in ClinVar (SCV000199244.4; Landrum et al., 2016). The V338M variant is not observed in large population cohorts (Lek et al., 2016). A missense variant in the same residue (V338A) has been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), supporting the functional importance of this residue of the protein. Furthermore, the V338M variant is located in the myosin motor domain, a region enriched with missense variants reported in association with cardiomyopathy (Kelly et al., 2018). However, the V338M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. In summary, V338M in the MYH7 gene is interpreted as a likely pathogenic variant. -
Likely pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Apr 17, 2013	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.Val338Met (c.1012G>A) in MYH7. We have seen this variant in a family with HCM and it was present in multiple affected family members. The variant has been seen in a total of two unrelated HCM case (including the family in our center). In silico analysis with PolyPhen-2 predicts the variant to be possibly damaging. The valine at codon 338 is highly, though not completely, conserved across species; it is an isoleucine in platypus, chicken, and lizard. Neighboring amino acids are completely or highly conserved. We ere unable to find other variants reported in association with disease at this codon or nearby codons (+/- 5 positions). In total the variant has not been seen in ~6500 publicly available population datasets. There is no variation at codon 338 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of August 6th, 2012). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of August 6th, 2012). No published or laboratory control data is available. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2021

The p.V338M variant (also known as c.1012G>A), located in coding exon 10 of the MYH7 gene, results from a G to A substitution at nucleotide position 1012. The valine at codon 338 is replaced by methionine, an amino acid with highly similar properties. 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). This alteration has been detected in several individuals from hypertrophic cardiomyopathy (HCM) cohorts and cohorts referred for HCM genetic testing, and has shown some segregation with disease (Ho CY et al. Circ Cardiovasc Imaging, 2013 May;6:415-22; Captur G et al. Circ Cardiovasc Imaging. 2014;7:863-71; Homburger JR et al. Proc Natl Acad Sci USA. 2016;113(24):6701-6; Walsh R et al. Genet Med. 2017;19(2):192-203; Chida A et al. Heart Vessels. 2017 Jun;32(6):700-707; Mademont-Soler I et al. PLoS One. 2017 Aug;12(8):e0181465). In addition, this alteration has been detected by an outside laboratory in two probands reported to have HCM, and was reported to segregate with disease in multiple affected individuals from one family (LMM pers. comm.). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.56
CardioboostCm	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Benign	0.079
Eigen_PC	Benign	-0.051
FATHMM_MKL	Benign	0.24	N
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.9	N
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.59	P
Vest4		0.56
MutPred		0.70		Gain of catalytic residue at D333 (P = 0.0098);
MVP		0.96
MPC		2.0
ClinPred		0.92	D
GERP RS		4.0
Varity_R		0.57
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs727503271; hg19: chr14-23899110;