rs201865159
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP2PP3_Moderate
The NM_000257.4(MYH7):c.5494C>T(p.Arg1832Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000384 in 1,612,948 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 (★★).
Frequency
Consequence
NM_000257.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152212Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000359 AC: 9AN: 250790Hom.: 0 AF XY: 0.0000369 AC XY: 5AN XY: 135642
GnomAD4 exome AF: 0.0000397 AC: 58AN: 1460736Hom.: 0 Cov.: 34 AF XY: 0.0000385 AC XY: 28AN XY: 726760
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152212Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74352
ClinVar
Submissions by phenotype
not provided Uncertain:7
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In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25637381, 21424860, 21310275, 23299917, 23861362, 21839045, 22337857, 34426522, 19293840, 30847666, 34542152) -
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Cardiomyopathy Uncertain:2
This missense variant replaces arginine with cysteine at codon 1832 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 an individual affected with dilated cardiomyopathy (PMID: 19293840) and in two siblings affected with skeletal myopathy and left ventricular non-compaction (Moore et al., 2018). This variant has been observed in an individual with hypertrophic cardiomyopathy, who also carried a pathogenic mutation in the MYBPC3 gene (PMID: 21839045). This variant has been identified in 9/250790 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 arginine with cysteine at codon 1832 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 an individual affected with dilated cardiomyopathy (PMID: 19293840) and in two siblings affected with skeletal myopathy and left ventricular non-compaction (Moore et al., 2018). This variant has been observed in an individual with hypertrophic cardiomyopathy, who also carried a pathogenic mutation in the MYBPC3 gene (PMID: 21839045). This variant has been identified in 9/250790 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. -
Primary dilated cardiomyopathy Uncertain:2
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not specified Uncertain:1
Variant summary: MYH7 c.5494C>T (p.Arg1832Cys) results in a non-conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 250790 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5494C>T has been reported in the literature in an individual(s) affected with Dilated Cardiomyopathy (e.g. Moller_2009). This result does not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 19293840). ClinVar contains an entry for this variant (Variation ID: 161322). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Dilated cardiomyopathy 1S;C3495498:Hypertrophic cardiomyopathy 1 Uncertain:1
The c.5494C>T variant in MYH7 has previously been reported in one individual with idiopathic dilated cardiomyopathy [PMID: 19293840] and it has been deposited in ClinVar [ClinVar ID: 161322] as variant of uncertain significance by multiple submitters. The c.5494C>T variant is observed in 14 alleles (~0.002% minor allelefrequency with 0 homozygote) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases, which might include individuals with adult onset cardiac phenotypes. The c.5494C>T variant in MYH7 is located in exon 37 of this 40-exon gene, and is predicted to replace an evolutionarily conserved arginine amino acid with cysteine at position 1832 (p.(Arg1832Cys) in the C-terminalrod domain [PMID:35854315] of the encoded protein. In silico predictions provide supporting evidence for damaging effect for the p.(Arg1832Cys) variant [CADD v1.6= 27.4, REVEL = 0.767]; however, there are no functional studies to support or refute these predictions. Based on available evidence this c.5494C>Tp.(Arg1832Cys) variant identified in MYH7 is classified as a Variant of Uncertain Significance. -
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
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Hypertrophic cardiomyopathy Uncertain:1
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1832 of the MYH7 protein (p.Arg1832Cys). This variant is present in population databases (rs201865159, gnomAD 0.006%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 19293840). ClinVar contains an entry for this variant (Variation ID: 161322). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -
Cardiovascular phenotype Uncertain:1
The p.R1832C variant (also known as c.5494C>T), located in coding exon 35 of the MYH7 gene, results from a C to T substitution at nucleotide position 5494. The arginine at codon 1832 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been detected in an individual with dilated cardiomyopathy (Møller DV et al. Eur J Hum Genet. 2009 Oct;17:1241-9), and in an individual with hypertrophic cardiomyopathy who also had a frameshift mutation in MYBPC3 (Maron BJ et al. Heart Rhythm. 2012 Jan;9:57-63). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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