rs121913634

chr14-23425372-T-Achr14-23425372-T-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_000257.4(MYH7):c.2333A>T(p.Asp778Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. D778N) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:4
• Conservation: PhyloP100: 7.61

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 13 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 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 chr14-23425371-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 188615.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, MYH7
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 14-23425372-T-A is Pathogenic according to our data. Variant chr14-23425372-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 454354.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23425372-T-A is described in Lovd as [Likely_pathogenic]. Variant chr14-23425372-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4	c.2333A>T	p.Asp778Val	missense_variant	21/40	ENST00000355349.4
MYH7	NM_001407004.1	c.2333A>T	p.Asp778Val	missense_variant	20/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4	c.2333A>T	p.Asp778Val	missense_variant	21/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152124 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74308

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Hypertrophic cardiomyopathy Pathogenic:2

Likely pathogenic, no assertion criteria provided	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Dec 11, 2019	MYH7 Asp778Val has been identified previously in 2 HCM probands (Capek P, et al., 2011; Van Driest SL, et al., 2004). The variant is present at a low frequency in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). We have identified this variant in a single HCM proband who presented with asymmetric hypertrophy (Ingles et al 2017). This proband also carries a second MYH7 variant (Arg1818Val) in trans with this MYH7 Asp778Val. A deceased family member was diagnosed with HCM at post-mortem and only MYH7 Asp778Val was found to segregate to the decedent. Computational tools SIFT, PolyPhen-2, PolyPhen-HCM and MutationTaster predict this variant to have a deleterious effect. Interestingly another variant at this position (c.2334C>G Asp778Glu) has been classified as pathogenic, suggesting that an amino acid substitution at this site may not be tolerated. In a large HCM population study Walsh et al., showed that MYH7 variants identified in HCM cases were found to cluster between amino acids 181- 937 (2017), this implies that variants in this region are likely to cause a HCM phenotype. Based on the adapted ACMG guidelines (Kelly MA, et al., 2018) this variant is located in a known functional domain of MYH7 (PM1), is rare in the general population (PM2), and another variant at this position has been classified as pathogenic (PM5). It has also has been identified in more than 2 HCM probands (PS4_supporting) and in silico tools predict the variant to be deleterious (PP3), therefore we classify MYH7 Asp778Val as "likely pathogenic". -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 08, 2021	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp778 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11748309, 12707239, 22112859, 27247418). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 15358028, 21674835). ClinVar contains an entry for this variant (Variation ID: 454354). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with valine at codon 778 of the MYH7 protein (p.Asp778Val). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and valine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.6	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-7.5	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.98	D
Vest4		0.98
MutPred		0.79		Gain of MoRF binding (P = 0.0247);
MVP		0.99
MPC		2.5
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.68
gMVP		0.99

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: rs121913634; hg19: chr14-23894581;