14-23431584-C-T

Position:

chr14-23431584-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_000257.4(MYH7):c.732+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

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:11

Conservation

PhyloP100: 6.00

Variant links:

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]

MYH7 links:

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ACMG classification

Classification made for transcript

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-T is Pathogenic according to our data. Variant chr14-23431584-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23431584-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH7	NM_000257.4 linkuse as main transcript	c.732+1G>A		splice_donor_variant, intron_variant		ENST00000355349.4	NP_000248.2	P12883
MYH7	NM_001407004.1 linkuse as main transcript	c.732+1G>A		splice_donor_variant, intron_variant			NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.732+1G>A		splice_donor_variant, intron_variant		1	NM_000257.4	ENSP00000347507.3		P12883

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251490

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 19, 2024	Reported in probands with Ebstein anomaly, including a fetus with additional features of left ventricular hypertrophy, dilation, and noncompaction (PMID: 35209905, 27788187); Not observed at significant frequency in large population cohorts (gnomAD); Predicted to cause exon skipping that would disrupt the myosin motor domain; however, in the absence of definitive functional studies, the actual effect of this sequence change is unknown; Canonical splice site variant expected to result in aberrant splicing; other splice site variants in the MYH7 gene have been reported in association with cardiomyopathy (HGMD); This variant is associated with the following publications: (PMID: 25525159, 29300372, 18506004, 21551322, 12749056, 22859017, 35209905, 27788187, 30847666, 34758253, 35877568, 33500567, 36292635, 23861362) -

Dilated cardiomyopathy 1S

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

New York Genome Center

Jan 16, 2020

The c.732+1G>A variant identified in the MYH7 gene substitutes a completely conserved Guanine for Adenine at the +1 canonical splice site in intron8/39 (+1 splice donor of exon 8). This variant is found with low frequency in gnomAD (1 heterozygote, 0 homozygotes; allele frequency: 3.98e-6), suggesting it is not a common benign variant in the populations represented in this database. This variant is reported as Pathogenic in ClinVar (VarID:14127), and has been identified in several individuals and families in the literature with left ventricular noncompaction and noncompaction cardiomyopathy [PMID: 18506004; PMID: 21551322; PMID: 22859017; PMID: 23861362]. Given its position at a canonical splice donor site, its low frequency in population databases, and presence in affected individuals and families in the literature in which it segregates with disease, the c.732+1G>A variant identified in the MYH7 gene is reported here as Pathogenic. -

Left ventricular noncompaction cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

- -

Left ventricular noncompaction

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 31, 2017

c.732+1G>A (MYH7; NM_000257.2; Chr14g.23900793C>T; GRCh37): The c.732+1G>A (also reported as c.818+1G>A) variant in MYH7 has been reported in 3 adults and 1 inf ant with LVNC, segregated with disease in 9 affected relatives from 3 families ( Klaassen 2008, Hoedemaeker 2013, Ng 2013). It has been identified in 1/17348 Eas t Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.br oadinstitute.org/; dbSNP rs397516266). This variant occurs in the invariant regi on (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. In summary, this variant meet s criteria to be classified as pathogenic for LVNC in an autosomal dominant mann er based upon predicted impact on the protein, presence in multiple affected ind ividuals, significant segregation evidence, and an extremely low frequency in th e general population. -

Left ventricular noncompaction 5

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 03, 2008

- -

Hypertrophic cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 08, 2023

This sequence change affects a donor splice site in intron 8 of the MYH7 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), however the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in MYH7 cause disease. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individual(s) with Ebstein anomaly and left ventricular non-compaction (PMID: 18506004, 22859017, 27788187). It has also been observed to segregate with disease in related individuals. This variant is also known as c.818+1G>A. ClinVar contains an entry for this variant (Variation ID: 14127). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 12, 2023

The c.732+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 6 of the MYH7 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, this alteration has been reported in several individuals with left ventricular non-compaction (LVNC) and segregated with disease in two families (Klaassen S et al. Circulation, 2008 Jun;117:2893-901; Hoedemaekers YM et al. Ultrasound Obstet Gynecol, 2013 Mar;41:336-9; Kelly MA et al. Genet Med, 2018 Mar;20:351-359; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Hypertrophic cardiomyopathy 1

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Genomics England Pilot Project, Genomics England

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

0.86

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.95

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over