14-23415267-C-T
Variant summary
Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PP2PP3_Strong
The NM_000257.4(MYH7):c.5287G>A(p.Ala1763Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000112 in 1,614,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1763S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000257.4 missense
Scores
Clinical Significance
Conservation
Publications
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ACMG classification
Our verdict: Likely_pathogenic. The variant received 7 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MYH7 | NM_000257.4 | c.5287G>A | p.Ala1763Thr | missense_variant | Exon 37 of 40 | ENST00000355349.4 | NP_000248.2 | |
| MYH7 | NM_001407004.1 | c.5287G>A | p.Ala1763Thr | missense_variant | Exon 36 of 39 | NP_001393933.1 | ||
| MHRT | NR_126491.1 | n.-183C>T | upstream_gene_variant |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MYH7 | ENST00000355349.4 | c.5287G>A | p.Ala1763Thr | missense_variant | Exon 37 of 40 | 1 | NM_000257.4 | ENSP00000347507.3 | ||
| MYH7 | ENST00000713768.1 | c.5287G>A | p.Ala1763Thr | missense_variant | Exon 37 of 41 | ENSP00000519070.1 | ||||
| MYH7 | ENST00000713769.1 | c.5287G>A | p.Ala1763Thr | missense_variant | Exon 36 of 39 | ENSP00000519071.1 | ||||
| ENSG00000258444 | ENST00000557368.1 | n.-72C>T | upstream_gene_variant | 3 |
Frequencies
GnomAD3 genomes 0.000105 AC: 16AN: 152248Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000676 AC: 17AN: 251494 AF XY: 0.0000662 show subpopulations
GnomAD4 exome AF: 0.000112 AC: 164AN: 1461894Hom.: 0 Cov.: 34 AF XY: 0.000102 AC XY: 74AN XY: 727248 show subpopulations
Age Distribution
GnomAD4 genome 0.000112 AC: 17AN: 152366Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9AN XY: 74516 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy Uncertain:4
The p.Ala1763Thr variant in MYH7 has been reported in 1 infant with HCM, who also carried a pathogenic variant in MYBC3, and 6 individuals with cardiomyopathy (5 with HCM, and 1 with DCM: Berge 2014, Bos 2014, Alfares 2015, Walsh 2017, LMM data). One of the individuals with HCM carried an additional pathogenic variant in MYH7 sufficient to explain their disease. This variant has also been identified in 14/126724 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs727504355). This variant was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Ala1763Thr variant is uncertain. ACMG/AMP criteria applied: BS1_P.
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1763 of the MYH7 protein (p.Ala1763Thr). This variant is present in population databases (rs727504355, gnomAD 0.01%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy, dilated cardiomyopathy or sudden death (PMID: 24111713, 24793961, 25611685, 26468400, 27532257, 27600940, 28790153, 28807990). ClinVar contains an entry for this variant (Variation ID: 177846). 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 with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Cardiomyopathy Uncertain:3
This missense variant replaces alanine with threonine at codon 1763 of the MYH7 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with hypertrophic cardiomyopathy (PMID: 31513939, 24111713, 24793961, 25611685, 27532257, 27600940, 28790153, 33495597, 38489124), in an individual affected with dilated cardiomyopathy (PMID: 26468400), and in an individual affected with sudden unexplained death (PMID: 28807990). One individual affected with hypertrophic cardiomyopathy also carried a pathogenic variant in a different gene (PMID: 27600940). This variant has been identified in 21/282898 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
This missense variant replaces alanine with threonine at codon 1763 of the MYH7 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with hypertrophic cardiomyopathy (PMID: 24111713, 24793961, 25611685, 27532257, 27600940, 28790153), in one individual affected with dilated cardiomyopathy (PMID: 26468400), and in an individual affected with sudden unexplained death (PMID: 28807990). One individual affected with hypertrophic cardiomyopathy carried a pathogenic variant in a different gene in addition to this variant (PMID: 27600940). This variant has been identified in 21/282898 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
not provided Uncertain:3
MYH7: PM2, PP3
Dilated cardiomyopathy 1S Uncertain:2
This variant is classified as VUS-3B. Evidence in support of pathogenic classification: Variant is present in gnomAD <0.01 (v4: 181 heterozygote(s), 0 homozygote(s)); Missense variant predicted to be damaging by in silico tool(s) or highly conserved with a major amino acid change. Additional information: Variant is predicted to result in a missense amino acid change from alanine to threonine; This variant is heterozygous; This gene is associated with both recessive and dominant disease. Disease associated with this gene usually has autosomal dominant inheritance; however, a recessive inheritance pattern has been observed in severe cases (OMIM); Alternative amino acid change(s) at the same position are present in gnomAD (highest allele count: v4: 6 heterozygote(s), 0 homozygote(s)); Previous evidence of pathogenicity for this variant is inconclusive. This variant has been classified as a VUS by clinical laboratories in ClinVar. This variant has also been reported in the literature in individuals with sudden death or hypertrophic/dilated cardiomyopathy. At least one of these reported individuals had an alternative pathogenic variant (PMIDs: 26468400, 27600940, 28408708, 28807990); No published functional evidence has been identified for this variant; Another missense variant(s) comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. p.(Ala1763Ser) has been classified as a VUS by a diagnostic laboratory in ClinVar; Variant is located in the annotated myosin tail domain (DECIPHER); The mechanism of disease for this gene is not clearly established; however, missense variants have been proposed to act in a dominant negative manner (PMID: 24714796); The condition associated with this gene has incomplete penetrance (PMID: 29300372); This variant has been shown to be paternally inherited (by trio analysis).
Hypertrophic cardiomyopathy 1 Uncertain:2
The Ala1763Thr variant has been previously reported in 4 SUD cases (Dewar LJ et al., 2017), 3 DCM cases (Broch K, et al., 2018; LMM, Pers. Comm.; Phosphorus inc, ClinVar SCV000679791), 1 LVNC case (Blueprint, ClinVar SCV000264098), 3 myopathy cases (Phosphorus inc, ClinVar SCV000679793-5) and 7 HCM cases (Walsh et al., 2017; Cecconi M, et al., 2016; Bos JM, et al., 2014; Berge & Leren, 2014; Invitae, ClinVar SCV000546187; Phosphorus inc, ClinVar SCV000679792). It is present at an elevated frequency of 0.0000685 in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). The MYH7 Ala1736Thr variant occurs in a conserved region, and in silico tools (SIFT, PolyPhen2, MutationTaster and CADD) support a damaging role for this variant. We have identified this variant in a single HCM proband who has no family history of disease (Ingles J et al., 2017; Burns C, et al., 2017). Based on the adapted ACMG guidelines (Kelly MA, et al., 2018), this variant is not rare in the general population and therefore probands cannot be counted as evidence. In silico tools predict it to deleterious (PP3), therefore we classify MYH7 Ala1763Thr as a variant of 'uncertain significance'.
Myopathy, myosin storage, autosomal recessive Uncertain:1
MYH7-related disorder Uncertain:1
The MYH7 c.5287G>A variant is predicted to result in the amino acid substitution p.Ala1763Thr. This variant was reported in multiple individuals with hypertrophic cardiomyopathy or dilated cardiomyopathy (Berge et al. 2014. PubMed ID: 24111713; Broch et al. 2015. PubMed ID: 26468400; Table S1B, Walsh et al. 2017. PubMed ID: 27532257; Table S2, Burns et al. 2017. PubMed ID: 28790153; Table S2, Robyns et al. 2020. PubMed ID: 31513939), as well as in four pediatric cases of sudden unexplained death (Dewar et al. 2017. PubMed ID: 28807990). However, another cohort study found this variant only in eight individuals in the control group and none of the hypertrophic cardiomyopathy patients (Table S6, Park et al. 2022. PubMed ID: 34542152). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/177846/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
not specified Uncertain:1
Variant summary: MYH7 c.5287G>A (p.Ala1763Thr) results in a non-conservative amino acid change located in the Myosin tail domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251494 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MYH7 causing Cardiomyopathy (6.8e-05 vs 0.0013), allowing no conclusion about variant significance. c.5287G>A has been reported in the literature in individuals affected with HCM, DCM, or sudden unexpected death. These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Co-occurrences with a pathogenic variant has been reported (TTN c.48868C>T, p.Arg16290X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Myosin storage myopathy Uncertain:1
MYH7-related skeletal myopathy Uncertain:1
Congenital myopathy with fiber type disproportion;C1834481:Dilated cardiomyopathy 1S;C1842160:Myosin storage myopathy;C1850709:Myopathy, myosin storage, autosomal recessive;C3495498:Hypertrophic cardiomyopathy 1;C4552004:MYH7-related skeletal myopathy Uncertain:1
Left ventricular noncompaction cardiomyopathy Uncertain:1
Cardiovascular phenotype Uncertain:1
The p.A1763T variant (also known as c.5287G>A), located in coding exon 35 of the MYH7 gene, results from a G to A substitution at nucleotide position 5287. The alanine at codon 1763 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in individuals with hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and sudden death; however, clinical details were limited (Bos JM et al. Mayo Clin. Proc., 2014 Jun;89:727-37; Berge KE et al. Clin. Genet., 2014 Oct;86:355-60; Broch K et al. Open Heart, 2015 Oct;2:e000271; Alfares AA et al. Genet. Med., 2015 Nov;17:880-8; Dewar LJ et al. Circ Cardiovasc Genet. 2017 Aug;10(4); Ramchand J et al. J Am Heart Assoc. 2020 01;9(2):e013346). In one HCM case, the individual also had a second alteration in another cardiac-related gene (Cecconi M et al. Int. J. Mol. Med., 2016 Oct;38:1111-24). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at