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
Consequence
NM_000257.4 splice_region, synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH7 | NM_000257.4 | c.5655G>A | p.Ala1885= | splice_region_variant, synonymous_variant | 38/40 | ENST00000355349.4 | |
MYH7 | NM_001407004.1 | 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 | c.5655G>A | p.Ala1885= | splice_region_variant, synonymous_variant | 38/40 | 1 | NM_000257.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152184Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251438Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135890
GnomAD4 exome AF: 0.0000383 AC: 56AN: 1461826Hom.: 0 Cov.: 33 AF XY: 0.0000440 AC XY: 32AN XY: 727214
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152184Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74344
ClinVar
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at