14-23431804-G-A

Position:

• chr14-23431804-G-A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The ENST00000355349.4(MYH7):​c.596C>T​(p.Ala199Val) variant causes a missense change involving the alteration of a 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. A199T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYH7 ENST00000355349.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.92

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 19 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in ENST00000355349.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-23431805-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1806336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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, 0.962
• PP5: Variant 14-23431804-G-A is Pathogenic according to our data. Variant chr14-23431804-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 177692.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23431804-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH7	NM_000257.4	c.596C>T	p.Ala199Val	missense_variant	7/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.596C>T	p.Ala199Val	missense_variant	6/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.596C>T	p.Ala199Val	missense_variant	7/40	1	NM_000257.4	ENSP00000347507.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 16, 2018	The A199V likely pathogenic variant in the MYH7 gene has previously been reported in association with HCM (Alfares et al., 2015; Adler et al., 2016; Walsh et al., 2017). In addition, Pan et al. (2012) identified A199V in one patient with cardiomyopathy and found that this variant segregated with disease in >5 affected individuals within a single kindred, although specific segregation information was not provided. This variant was also identified in two unrelated individuals with childhood onset HCM referred for genetic testing at GeneDx. This variant is not observed in large population cohorts (Lek et al., 2016). Although the A199V 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 a deleterious effect. In addition, this variant is located in the myosin motor domain, a region enriched with missense variants reported in association with HCM (Walsh et al., 2017; Kelly et al., 2018). -
Likely pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jan 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. p.Ala199Val (c.596C>T). Data on this variant is reviewed below. We feel there is sufficiently strong co-segregation within the patient's own family to consider it likely pathogenic. I could find no published reports of this variant. Nearby missense variants have been reported in association with disease, including p.Ala196Thr (Woo et al 2003) and p.Arg204His (Richard et al 2003). The alanine at position 199 is completely conserved across species. In silico analysis with PolyPhen 2 predicts the variant to be probably damaging, while mutation taster predicts it to be disease causing. The variant is not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~10,000 alleles from Caucasian and African American individuals (as of December 1st, 2011). It is not listed in dbSNP or 1000 genomes (as of December 1st, 2011). -

Hypertrophic cardiomyopathy Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 18, 2020	The p.Ala199Val variant in MYH7 has been identified by our laboratory in at least 3 individuals with HCM and segregated with disease in several affected relatives (including 3 obligate carriers) from 1 family (Pan 2012, Alfares PMID: 25611685, Walsh 2017 PMID: 27532257, LMM unpublished data and personal communication). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 177693) was absent from large population studies. Computational prediction tools and conservation analyses are consistent with pathogenicity. This variant lies in the head region of the protein and missense variants in this region are statistically more likely to be disease-associated (Walsh 2017 PMID 27532257). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PM2_Supporting, PS4_Supporting, PP1_Strong, PP3, PM1. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 02, 2023	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). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. ClinVar contains an entry for this variant (Variation ID: 177692). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 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 199 of the MYH7 protein (p.Ala199Val). -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 23, 2024

The p.A199V variant (also known as c.596C>T), located in coding exon 5 of the MYH7 gene, results from a C to T substitution at nucleotide position 596. The alanine at codon 199 is replaced by valine, an amino acid with 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 reported in individuals with hypertrophic cardiomyopathy (HCM) (Adler A et al. Circ Arrhythm Electrophysiol, 2016 Jan;9:e003440; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Ho CY et al. Circulation, 2018 Oct;138:1387-1398; Sepp R et al. Diagnostics (Basel), 2022 May;12:[ePub ahead of print]). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	0.96
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	3.0	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.017	D
Polyphen		0.93	P
Vest4		0.93
MutPred		0.72		Gain of catalytic residue at A199 (P = 5e-04);
MVP		0.98
MPC		2.1
ClinPred		0.99	D
GERP RS		3.1
Varity_R		0.90
gMVP		0.98

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: rs727504283; hg19: chr14-23901013; COSMIC: COSV62519602;