ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.3412C>G (p.Pro1138Ala) (rs915209025)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000462309 SCV000541567 uncertain significance Brugada syndrome 8 2016-08-20 criteria provided, single submitter clinical testing This sequence change replaces proline with alanine at codon 1138 of the HCN4 protein (p.Pro1138Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a HCN4-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000621104 SCV000737517 uncertain significance Cardiovascular phenotype 2016-06-22 criteria provided, single submitter clinical testing The p.P1138A variant (also known as c.3412C>G), located in coding exon 8 of the HCN4 gene, results from a C to G substitution at nucleotide position 3412. The proline at codon 1138 is replaced by alanine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6472 samples (12944 alleles) with coverage at this position. This amino acid position is poorly conserved in available vertebrate species, and alanine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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