rs397516206

Positions:

• chr14-23417600-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_000257.4(MYH7):​c.4256A>G​(p.His1419Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 6.06

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]

MHRT (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a helix (size 64) in uniprot entity MYH7_HUMAN there are 16 pathogenic changes around while only 1 benign (94%) in NM_000257.4
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH7	NM_000257.4	c.4256A>G	p.His1419Arg	missense_variant	31/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.4256A>G	p.His1419Arg	missense_variant	30/39		NP_001393933.1
MHRT	NR_126491.1	n.*5T>C		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.4256A>G	p.His1419Arg	missense_variant	31/40	1	NM_000257.4	ENSP00000347507.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 08, 2013

Variant classified as Uncertain Significance - Favor Pathogenic. The His1419Arg variant has not been reported in the literature nor previously identified by our laboratory. This variant has also not been identified in large European America n and African American populations by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS), which increases the likelihood that the variant is pathogenic. However, it may be present in other populations. The change to argin ine (Arg) was predicted to be pathogenic using a computational tool clinically v alidated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). Other computational analyses (biochemica l amino acid properties, AlignGVGD, PolyPhen2, and SIFT) do not provide strong s upport for or against an impact to the protein. In summary, this data is consist ent with a pathogenic role but is insufficient to establish this with certainty. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 26, 2024

Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function -

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2019

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. A computational algorithm designed to assess the pathogenicity of variants in MYH7 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). This variant has not been reported in the literature in individuals with MYH7-related disease. ClinVar contains an entry for this variant (Variation ID: 43002). This variant is not present in population databases (ExAC no frequency). This sequence change replaces histidine with arginine at codon 1419 of the MYH7 protein (p.His1419Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 18, 2023

The p.H1419R variant (also known as c.4256A>G), located in coding exon 29 of the MYH7 gene, results from an A to G substitution at nucleotide position 4256. The histidine at codon 1419 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
CardioboostCm	Uncertain	0.61
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.71	T
M_CAP	Pathogenic	0.77	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Uncertain	2.6	M
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.46
Sift	Uncertain	0.018	D
Sift4G	Benign	0.36	T
Polyphen		0.79	P
Vest4		0.56
MutPred		0.44		Gain of MoRF binding (P = 0.0113);
MVP		0.92
MPC		1.5
ClinPred		0.87	D
GERP RS		5.0
Varity_R		0.42
gMVP		0.94

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: rs397516206; hg19: chr14-23886809;