14-23424875-C-G

Position:

• chr14-23424875-C-G

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.2573G>C​(p.Arg858Pro) 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. R858G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.761

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, 13 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 chr14-23424876-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 164324.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, 0.989
• PP5: Variant 14-23424875-C-G is Pathogenic according to our data. Variant chr14-23424875-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 520277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23424875-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4	c.2573G>C	p.Arg858Pro	missense_variant	22/40	ENST00000355349.4
MYH7	NM_001407004.1	c.2573G>C	p.Arg858Pro	missense_variant	21/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4	c.2573G>C	p.Arg858Pro	missense_variant	22/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 09, 2021

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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). This variant disrupts the p.Arg858 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15358028, 24093860, 28498465). 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. ClinVar contains an entry for this variant (Variation ID: 520277). This missense change has been observed in individuals with clinical features of hypertrophic cardiomyopathy (HCM) (PMID: 27247418, 27532257). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 858 of the MYH7 protein (p.Arg858Pro). -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 15, 2016

The p.R858P variant (also known as c.2573G>C), located in coding exon 20 of the MYH7 gene, results from a G to C substitution at nucleotide position 2573. The arginine at codon 858 is replaced by proline, an amino acid with dissimilar properties. This alteration has been previously reported in individuals with hypertrophic cardiomyopathy (HCM) (Girolami F et al. J Cardiovasc Med. 2006;7(8):601-7; Olivotto I et al. J Am Coll Cardiol. 2011;58(8):839-48; Witjas-Paalberends ER et al. Cardiovasc Res. 2013;99(3):432-41). In addition, other alterations at this amino acid position (p.R858G, p.R858C and p.R858H) have also been reported in individuals with HCM (Van Driest SL et al. J Am Coll Cardiol. 2004;44(3):602-10; Song L et al. Clin Chim Acta. 2005;351(1-2):209-16; Chiou KR et al. J Cardiol. 2015;65(3):250-6; Lopes LR et al. Heart. 2015; 101(4):294-301; LMM, unpublished data in ClinVar). This variant was previously reported in the SNPDatabase as rs2856897. This variant was not reported in population based cohorts in the following databases: Exome Aggregation Consortium (ExAC), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved through mammals. 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	0.85
CardioboostCm	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Benign	0.013
Eigen_PC	Benign	-0.070
FATHMM_MKL	Benign	0.45	N
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	0.56	N
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.014	D
Polyphen		0.77	P
Vest4		0.90
MutPred		0.82		Loss of MoRF binding (P = 0.0068);
MVP		0.91
MPC		2.2
ClinPred		0.97	D
GERP RS		3.8
Varity_R		0.76
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: rs2856897; hg19: chr14-23894084;