14-23431584-C-G

Position:

• chr14-23431584-C-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_000257.4(MYH7):​c.732+1G>C variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH7 NM_000257.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.00

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.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.015840221 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-23431584-C-G is Pathogenic according to our data. Variant chr14-23431584-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 849269.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.732+1G>C		splice_donor_variant, intron_variant		ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.732+1G>C		splice_donor_variant, intron_variant			NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.732+1G>C		splice_donor_variant, intron_variant		1	NM_000257.4	ENSP00000347507.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 20, 2023

The MYH7 c.732+1G>C variant (rs730880850), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID:849269). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, other changes at this splice site have been reported in two families with left ventricular noncompaction and in one individual with Ebstein anomaly and are considered to be disease causing (Klaassen 2008, Sicko 2016). This variant disrupts the canonical splice donor site of intron 8, which is likely to negatively impact gene function. Based on available information, this variant is considered to be likely pathogenic. References: Klaassen S et al. Mutations in sarcomere protein genes in left ventricular noncompaction. Circulation. 2008 Jun 3;117(22):2893-901. PMID: 18506004. Sicko RJ et al. Genetic Variants in Isolated Ebstein Anomaly Implicated in Myocardial Development Pathways. PLoS One. 2016 Oct 27;11(10):e0165174. PMID: 27788187. -

Hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 08, 2020

Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic. Disruption of this splice site has been observed to segregate with left ventricular noncompaction in families (PMID: 18506004) and has been reported in an individual affected with Ebstein anomaly (PMID: 27788187). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 8 of the MYH7 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Pathogenic	0.86
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.96	D
GERP RS		3.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs730880850; hg19: chr14-23900793;