ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.584C>T (p.Ala195Val) (rs201375192)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000170947 SCV000055271 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
GeneDx RCV000170947 SCV000223507 uncertain significance not provided 2014-10-31 criteria provided, single submitter clinical testing p.Ala195Val (GCT>GTT): c.584 C>T in exon 1 of the HCN4 gene (NM_005477.2). The A195V variant has been reported in one case of sudden infant death syndrome (Evans et al., 2013). This substitution occurs at a position that is conserved in most mammals and the A195V variant was not observed in approximately 5,900 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. However, the 1000 Genomes Project reports A195V was observed in 0.5% of Asian alleles and 0.5% of European alleles, indicating it may be a rare (benign) variant in these populations. The A195V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, missense mutations in nearby residues have not been reported, indicating this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in ARRHYTHMIA panel(s).
Ambry Genetics RCV000622073 SCV000736152 uncertain significance Cardiovascular phenotype 2017-12-07 criteria provided, single submitter clinical testing The p.A195V variant (also known as c.584C>T), located in coding exon 1 of the HCN4 gene, results from a C to T substitution at nucleotide position 584. The alanine at codon 195 is replaced by valine, an amino acid with similar properties. This alteration was reported once in a sudden infant death cohort (Evans A et al. Hum. Pathol., 2013 Sep;44:1730-6). This alteration has also been reported as a secondary cardiac variant in an exome cohort (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46). Based on data from gnomAD, the T allele has an overall frequency of approximately 0.037% (96/259274) total alleles studied. The highest observed frequency was 0.501% (93/18564) of East Asian alleles. This amino acid position is well conserved in available vertebrate species; however, valine 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.
Invitae RCV001084301 SCV001007226 benign Brugada syndrome 8 2020-11-15 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001117430 SCV001275616 likely benign Sick sinus syndrome 2, autosomal dominant 2017-06-14 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

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