14-23430954-C-G

Position:

• chr14-23430954-C-G

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The ENST00000355349.4(MYH7):​c.842G>C​(p.Arg281Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,800 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R281K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYH7 ENST00000355349.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.96

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 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in ENST00000355349.4
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.986
• PP5: Variant 14-23430954-C-G is Pathogenic according to our data. Variant chr14-23430954-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 181327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23430954-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH7	NM_000257.4	c.842G>C	p.Arg281Thr	missense_variant	10/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.842G>C	p.Arg281Thr	missense_variant	9/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.842G>C	p.Arg281Thr	missense_variant	10/40	1	NM_000257.4	ENSP00000347507	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461800 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 23, 2017

The Arg281Thr variant in the MYH7 gene has been reported in a large family with noncompaction of the ventricular myocardium (NVM). Budde B et al. (2007) reported that the Arg281Thr variant co-segregated with a noncompaction phenotype in the family with high clinical variability. Arg281Thr occurs in a conserved region of the protein, and in silico programs predict the variant destabilizes the myosin head. In many individuals in the family, other heart defects were seen along with noncompaction, including Ebstein's anomaly. Furthermore, the NHLBI ESP Exome Variant Server reports Arg281Thr was not observed in approximately 6,500 samples from individuals of European and African America backgrounds, indicating it is not a common benign variant in these populations. Based on currently available evidence, R281T is a strong candidate for a pathogenic variant. However, the possibility it is a rare benign variant cannot be excluded. -

Left ventricular noncompaction Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 03, 2015

The p.Arg281Thr variant in MYH7 has been reported in 1 German individual with LV NC, Ebstein's anomaly and ASD, and segregated with disease in 10 affected relati ves (Budde 2007). This variant has also been identified in 1 individual with HCM (Waldmuller 2008), and was absent from large population studies. Arginine (Arg) at position 281 is highly conserved in evolution, and the change to threonine ( Thr) was predicted to be pathogenic using a computational tool clinically valida ted by our laboratory. This tool's pathogenic prediction is estimated to be corr ect 94% of the time (Jordan 2011). In summary, this variant meets our criteria t o be classified as pathogenic (http://www.partners.org/personalizedmedicine/LMM) based upon segregation studies and absence from controls. -

Hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 06, 2023

For these reasons, this variant has been classified as Pathogenic. This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 281 of the MYH7 protein (p.Arg281Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant noncompaction of the ventricular myocardium (PMID: 18159245). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 181327). 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. 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). -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 30, 2023

The p.R281T variant (also known as c.842G>C), located in coding exon 8 of the MYH7 gene, results from a G to C substitution at nucleotide position 842. The arginine at codon 281 is replaced by threonine, an amino acid with similar properties. This variant arose de novo in one individual with left ventricular noncompaction cardiomyopathy (LVNC) and segregated with LVNC with variable expression in the proband's descendants, some of whom also had Ebstein's anomaly and/or septal defects (Budde BS et al. PLoS ONE, 2007 Dec;2:e1362). This variant has been reported in other individuals with LVNC (Mazzarotto F et al. Genet Med, 2021 May;23:856-864; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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	1.0
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.95	D
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	4.0	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.0020	B
Vest4		0.94
MutPred		0.85		Gain of catalytic residue at A279 (P = 0.0214);
MVP		0.86
MPC		2.5
ClinPred		0.99	D
GERP RS		3.6
Varity_R		0.93
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: rs730880856; hg19: chr14-23900163;