14-23424041-C-T

Position:

• chr14-23424041-C-T

Variant summary

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

The NM_000257.4(MYH7):​c.2788G>A​(p.Glu930Lys) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E930Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.74

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 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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 chr14-23424041-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 164312.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, 0.969
• PP5: Variant 14-23424041-C-T is Pathogenic according to our data. Variant chr14-23424041-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 42933.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23424041-C-T is described in Lovd as [Pathogenic]. Variant chr14-23424041-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.2788G>A	p.Glu930Lys	missense_variant	23/40	ENST00000355349.4
MYH7	NM_001407004.1	c.2788G>A	p.Glu930Lys	missense_variant	22/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4	c.2788G>A	p.Glu930Lys	missense_variant	23/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.736 Hom.: 2350

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 24, 2018	The E930K pathogenic variant in the MYH7 gene has been previously reported in multiple individuals with HCM (Marian et al., 1995; Woo et al., 2003; Song et al., 2005; Millat et al., 2010; Zou et al., 2013; Walsh et al., 2017). It has also been shown to segregate with HCM in multiple affected relatives from multiple families, as reported by Marian et al. (1995), Song et al. (2005), a different clinical laboratory (ClinVar SCV000059477.4, Landrum et al., 2016), and observed at GeneDx. The E930K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Moreover, likely pathogenic missense variants in nearby residues (E927K, D928N, E929K, E935K, E935V), and in the same residue (E930Q), have been reported in HGMD in association with cardiomyopathy (Stenson et al., 2014), further supporting the functional importance of this residue and region of the protein. Furthermore, the E930K variant is not observed in large population cohorts (Lek et al., 2016). -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	MYH7: PM2, PM5, PP1:Moderate, PS4:Moderate, PP2, PP4 -

Hypertrophic cardiomyopathy Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 19, 2014	The Glu930Lys variant in MYH7 has been reported in >10 individuals with HCM from 3 families and segregated with disease in 2 affected family members (Abchee 199 7, Woo 2003, Song 2005, Wang 2008). This variant was also identified by our labo ratory in 3 Caucasian individuals with HCM and segregated with disease in 5 affe cted individuals from 2 different families. Glutamic acid (Glu) at position 930 is highly conserved in mammals and across evolutionarily distant species and the change to Lysine (Lys) was predicted to be pathogenic using a computational too l clinically validated by our laboratory. This tool's pathogenic prediction is e stimated to be correct 94% of the time (Jordan 2011). In summary, this variant m eets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) based upon computational evidence, absence from controls, and segregation studi es. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 10, 2023	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. ClinVar contains an entry for this variant (Variation ID: 42933). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 9154300, 12975413, 19134269, 20800588, 27532257). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 930 of the MYH7 protein (p.Glu930Lys). -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 10, 2023

The p.E930K pathogenic mutation (also known as c.2788G>A), located in coding exon 21 of the MYH7 gene, results from a G to A substitution at nucleotide position 2788. The glutamic acid at codon 930 is replaced by lysine, 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 identified in one Chinese family with hypertrophic cardiomyopathy (HCM) and sudden cardiac death, segregating with disease in three affected individuals diagnosed with HCM (Song L et al. Clin. Chim. Acta. 2005;351:209-216). This alteration has also been reported in additional probands with HCM (Millat G etal. Eur J Med Genet 2010;53:261-267; Woo A etal. Heart 2003;89:1179-1185; Weissler-Snir A et al. Circ Cardiovasc Imaging, 2017 Feb;10:[ePub ahead of print]). Another alteration at the same codon, p.E930Q (c.2788G>C), has been detected in several individuals with HCM (Girolami F et al. J Cardiovasc Med (Hagerstown), 2006 Aug;7:601-7; Olivotto I et al. Mayo Clin Proc, 2008 Jun;83:630-8; Alfares AA et al. Genet Med, 2015 Nov;17:880-8; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Ware SM et al. J Am Heart Assoc, 2021 May;10:e017731; Burstein DS et al. Pediatr Res, 2021 May;89:1470-1476; Park J et al. Hum Mol Genet, 2022 Mar;31:827-837). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.79		Gain of catalytic residue at M932 (P = 2e-04);
MVP		0.99
MPC		1.2
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.73
gMVP		1.0

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: rs397516171; hg19: chr14-23893250;