rs730880855

chr14-23431425-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_000257.4(MYH7):c.789A>G(p.Ile263Met) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I263T) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 0.372

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 12 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 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 chr14-23431426-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 43106.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP2: Missense variant where missense usually causes diseases, MYH7
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 14-23431425-T-C is Pathogenic according to our data. Variant chr14-23431425-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 181326.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}. Variant chr14-23431425-T-C is described in Lovd as [Pathogenic]. Variant chr14-23431425-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4	c.789A>G	p.Ile263Met	missense_variant	9/40	ENST00000355349.4
MYH7	NM_001407004.1	c.789A>G	p.Ile263Met	missense_variant	8/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4	c.789A>G	p.Ile263Met	missense_variant	9/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Nov 06, 2015

- -

not specified Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Aug 26, 2015

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MYH7 p.Ile263Met (c.789A>G) The variant has been seen in at least one case. This variant was reported for by van Driest et al (2004) in a patient from their American HCM cohort. We could find no other reports. There is no segregation or functional data available on the variant. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. The isoleucine at codon 263 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon (p.Ile263Thr, which we consider likely disease causing) and a nearby codon (p.Gly256Glu). In total the variant has not been seen in ~5600 published controls and publicly available population datsets. There is no variation at codon 263 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~5500 Caucasian and African American individuals (as of 1/16/2012). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 1/16/2012). The variant was not observed in the following published control samples: 200 (van Driest et al 2004). -

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 20, 2019

This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with methionine at codon 263 of the MYH7 protein (p.Ile263Met). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and methionine. This variant has been observed in in individuals affected with hypertrophic cardiomyopathy (PMID: 15358028, 27532257). ClinVar contains an entry for this variant (Variation ID: 181326). 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. This variant disrupts the p.Ile263 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9829907, 24093860, 27247418, 27532257, 21425739, 12707239, 15008060). 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Benign	23
Dann	Benign	0.93
DEOGEN2	Pathogenic	0.91	D
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-2.3	N
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.0040	B
Vest4		0.98
MutPred		0.85		Gain of catalytic residue at I263 (P = 0.0097);
MVP		0.84
MPC		1.8
ClinPred		0.51	D
GERP RS		0.74
Varity_R		0.69
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs730880855; hg19: chr14-23900634;