rs587779392

Positions:

• chr14-23416122-A-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_000257.4(MYH7):​c.4835T>C​(p.Leu1612Pro) variant causes a missense change involving the alteration of a 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.73

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:51291): (myosin heavy chain associated RNA transcript) This gene encodes a spliced long non-coding RNA that may act as a cardioprotective agent in the heart. Based on a study of a similar gene in mouse, the encoded transcript may regulate chromatin remodeling by acting as a decoy to the BRG1 chromatin repressor complex thus preventing it from binding to its genomic targets. Blocking the actions of BRG1 could be crucial in protecting the heart from pathological hypertrophy. [provided by RefSeq, Dec 2014]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• 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). The gene has 341 curated pathogenic missense variants (we use a threshold of 10). The gene has 16 curated benign missense variants. GenCC has associacion of the 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, 0.926
• PP5: Variant 14-23416122-A-G is Pathogenic according to our data. Variant chr14-23416122-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 143213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH7	NM_000257.4	c.4835T>C	p.Leu1612Pro	missense_variant	34/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.4835T>C	p.Leu1612Pro	missense_variant	33/39		NP_001393933.1
MHRT	NR_126491.1	n.383A>G		non_coding_transcript_exon_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.4835T>C	p.Leu1612Pro	missense_variant	34/40	1	NM_000257.4	ENSP00000347507.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely 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

- -

Qualitative or quantitative defects of beta-myosin heavy chain (MYH7) Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Jan 24, 2023

The heterozygous p.Leu1612Pro variant in MYH7 was identified by our study in one individual with multiminicore myopathy and aortic aneurysm. The p.Leu1612Pro variant in MYH7 has been reported in one individual with Laing early distal myopathy (MPDI) (PMID: 24664454). This variant was assumed de novo in this one individual, but maternity and paternity have not been confirmed (PMID: 24664454). This variant has also been reported in ClinVar (Variation ID:143213) and has been interpreted as pathogenic by Royal Perth Hospital Neurogenetics Laboratory and as a variant of uncertain significance (VUS) by Invitae. This variant was absent from large population studies. The number of missense variants reported in MYH7 in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. Multiple variants in the same region as p.Leu1612Pro variant have been reported in association with disease in the literature, suggesting that this variant is in a hot spot and slightly supports pathogenicity ( PMID: 24664454). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal dominant MYH7-associated myopathy. ACMG/AMP Criteria applied: PS4_Supporting, PM1, PM2_Supporting, PM6_Supporting, PP3 (Richards 2015). -

Hypertrophic cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 23, 2023

This variant is not present in population databases (gnomAD no frequency). 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. 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. ClinVar contains an entry for this variant (Variation ID: 143213). This missense change has been observed in individuals with clinical features of autosomal dominant MYH7-related conditions (PMID: 24664454; Invitae). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1612 of the MYH7 protein (p.Leu1612Pro). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
CardioboostCm	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.64	T
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Pathogenic	3.5	H
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.74
MutPred		0.53		Loss of stability (P = 0.0024);
MVP		0.99
MPC		2.0
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.90
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: rs587779392; hg19: chr14-23885331;