rs587779393

chr14-23416020-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP2 PP3 PP5_Very_Strong

The NM_000257.4(MYH7):c.4937T>C(p.Leu1646Pro) 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.41

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 Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, MYH7
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.832
• PP5: Variant 14-23416020-A-G is Pathogenic according to our data. Variant chr14-23416020-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 143214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4	c.4937T>C	p.Leu1646Pro	missense_variant	34/40	ENST00000355349.4
MHRT	NR_126491.1	n.281A>G		non_coding_transcript_exon_variant	3/6
MYH7	NM_001407004.1	c.4937T>C	p.Leu1646Pro	missense_variant	33/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4	c.4937T>C	p.Leu1646Pro	missense_variant	34/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MYH7-related skeletal myopathy Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Neurogenetics Laboratory, Royal Perth Hospital

Jan 01, 2013

- -

Myosin storage myopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Oct 25, 2021

PS2, PM2, PP2, PP3, PP5 -

Hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 03, 2023

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1646 of the MYH7 protein (p.Leu1646Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of autosomal dominant distal myopathy (PMID: 24664454; Invitae). ClinVar contains an entry for this variant (Variation ID: 143214). 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. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
CardioboostCm	Uncertain	0.28
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D
Eigen	Benign	0.075
Eigen_PC	Benign	0.058
FATHMM_MKL	Benign	0.37	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Pathogenic	3.6	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.1	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.015	D
Polyphen		0.15	B
Vest4		0.75
MutPred		0.56		Gain of ubiquitination at K1651 (P = 0.0398);
MVP		0.85
MPC		1.8
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.82
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs587779393; hg19: chr14-23885229;