14-23414007-C-T

Position:

chr14-23414007-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3PP5

The NM_000257.4(MYH7):c.5655G>A(p.Ala1885=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000359 in 1,614,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

MYH7
NM_000257.4 splice_region, synonymous

Scores

Splicing: ADA: 0.9964

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:11U:2

Conservation

PhyloP100: -0.134

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

PP5

Variant 14-23414007-C-T is Pathogenic according to our data. Variant chr14-23414007-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 378215.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=8, Uncertain_significance=2, Likely_pathogenic=3}. Variant chr14-23414007-C-T is described in Lovd as [Pathogenic]. Variant chr14-23414007-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4 linkuse as main transcript	c.5655G>A	p.Ala1885=	splice_region_variant, synonymous_variant	38/40	ENST00000355349.4
MYH7	NM_001407004.1 linkuse as main transcript	c.5655G>A	p.Ala1885=	splice_region_variant, synonymous_variant	37/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.5655G>A	p.Ala1885=	splice_region_variant, synonymous_variant	38/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251438

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000383

AC:

AN:

1461826

Hom.:

Cov.:

AF XY:

0.0000440

AC XY:

AN XY:

727214

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:

0.0000486

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:11Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cardiomyopathy

Pathogenic:1Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 30, 2023	The c.5655G>A (p.Ala1885=) in the MYH7 gene is a synonymous variant located in last nucleotide of exon 38, which is part of the consensus splice site for this exon. Experimental studies have shown that this variant affects proper mRNA splicing, resulting in an in-frame skipping of exon 38 and a shortening of the encoded protein by 32 amino acids (PMID: 26782017, 27387980). This variant has been reported in two individuals: one with early onset muscular weakness and fiber-type disproportion (PMID: 26782017) and a second patient with an early infantile onset of respiratory muscle impairment and left bundle branch block (PMID: 27387980). Notably, several patients with different genomic variants but identical exon 38 skipping (c.5655+1G>A, c.5655+5G>C) also demonstrate cardiac manifestations in the form of dilated cardiomyopathy and left ventricular non-compaction (PMID: 30794915, 27387980). This variant has been observed at an ultra-low frequency in the general population (gnomAD database 3/251,438). For these reasons, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Apr 19, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 11, 2023	This synonymous variant alters the conserved c.G at the last nucleotide of exon 38 of the MYH7 gene and has been shown to cause aberrant splicing and in-frame skipping of exon 38 (p.1854_1885del) (PMID: 26782017, 27387980, 30794915). This variant is expected to result in the expression of a truncated protein missing a part of LMM domain, which is a C-terminal tail region that forms the thick filament backbone and interacts with other proteins (PMID: 25125180). This variant has been reported in two individuals affected with congenital myopathy without cardiac involvement (PMID: 26782017, 33333461) and in an individual affected with congenital myopathy with cardiac left bundle block (PMID: 27387980). The variant occurred de novo in two carriers (PMID: 26782017, 27387980). This variant has not been reported in individuals affected with hypertrophic cardiomyopathy. This variant has been identified in 3/251438 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, this variant may have adverse structural impact by disrupting RNA splicing, but its impact on MYH7 protein function remains unknown. While this variant has been observed in individuals with congenital myopathy, the available evidence is insufficient to determine the role of this variant in autosomal dominant hypertrophic cardiomyopathy conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hypertrophic cardiomyopathy 1

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 31, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Nov 06, 2019	The c.5655G>A (p.Ala1885=) in the MYH7 gene is a synonymous variant located in last nucleotide of exon 38, which is part of the consensus splice site for this exon. Experimental studies have shown that this variant affects proper mRNA splicing, resulting in an in-frame skipping of exon 38 and a shortening of the encoded protein by 32 amino acids (PMID: 26782017, 27387980). This variant has been reported in two individuals: one with early onset muscular weakness and fiber-type disproportion (PMID: 26782017) and a second patient with an early infantile onset of respiratory muscle impairment and left bundle branch block (PMID: 27387980). Notably, several patients with different genomic variants but identical exon 38 skipping (c.5655+1G>A, c.5655+5G>C) also demonstrate cardiac manifestations in the form of dilated cardiomyopathy and left ventricular non-compaction (PMID: 30794915, 27387980). This variant has been observed at an ultra-low frequency in the general population (gnomAD database 3/251,438). For these reasons, this variant has been classified as Likely Pathogenic. -

Dilated cardiomyopathy 1S

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 31, 2023

- -

MYH7-related skeletal myopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 31, 2023

- -

Myosin storage myopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 31, 2023

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 22, 2023

Identified as a de novo variant in a young adult with congenital myopathy and left bundle branch block (Fiorillo et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); RNA studies have shown that this variant damages the natural splice donor site in intron 38, leading to in-frame skipping of exon 38 and resulting in a truncated protein product (Pajusalu et al., 2016; Fiorillo et al., 2016); This variant is associated with the following publications: (PMID: 26782017, 27387980, 33240318, 34135346, 33333461, 30794915, 36264615, 34363016) -

Myopathy, myosin storage, autosomal recessive

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 31, 2023

- -

Hypertrophic cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 27, 2023

This sequence change affects codon 1885 of the MYH7 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MYH7 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs753392652, gnomAD 0.003%). This variant has been observed in individual(s) with MYH7-related myopathy (PMID: 26782017, 27387980). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 378215). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of skipping of exon 38, but is expected to preserve the integrity of the reading-frame (PMID: 26782017, 27387980). For these reasons, this variant has been classified as Pathogenic. -

MYH7-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Jan 16, 2020

ACMG classification criteria: PS3, PS4, PM2, PP5 -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 16, 2019

The c.5655G>A pathogenic mutation (also known as p.A1885A), located in coding exon 36 of the MYH7 gene, results from a G to A substitution at nucleotide position 5655. This nucleotide substitution does not change the alanine at codon 1885. However, this change occurs in the last base pair of coding exon 36, which makes it likely to have some effect on normal mRNA splicing. This alteration has been detected in multiple individuals with MYH7-related myopathies and reportedly arose de novo in three of the cases (Pajusalu S et al. Neuromuscul. Disord., 2016 Mar;26:236-9; Fiorillo C et al. Orphanet J Rare Dis, 2016 07;11:91; Invitae pers. comm.; GeneDx pers. comm.; Ambry internal data). RNA studies indicate that this variant disrupts normal splicing, leading to the in-frame skipping of exon 38 (Pajusalu S et al. Neuromuscul. Disord., 2016 Mar;26:236-9; Fiorillo C et al. Orphanet J Rare Dis, 2016 07;11:91). Internal structural assessment suggests that the predicted resulting in-frame deletion would disrupt the coiled-coil formation in the Assembly Competency Domain, which appears to be critical for thick filament assembly (Sohn RL et al. J. Mol. Biol., 1997 Feb;266:317-30; Delorenzi M et al. Bioinformatics, 2002 Apr;18:617-25; Gruber M et al. J. Struct. Biol., 2006 Aug;155:140-5; Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation for MYH7-related skeletal myopathy; however, the association with cardiomyopathy is unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.87

SpliceAI score (max)

0.030

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

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