ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.2701G>A (p.Ala901Thr) (rs201742383)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000464894 SCV000541553 likely benign Brugada syndrome 8 2020-10-13 criteria provided, single submitter clinical testing
GeneDx RCV000480340 SCV000574427 uncertain significance not provided 2018-01-08 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the HCN4 gene. Although the A901T variant has not been published to our knowledge, it has been observed both independently, and in conjunction with additional cardiogenetic variants, in other individuals referred for cardiac genetic testing at GeneDx, although no segregation data are available to further clarify the role of this variant in disease. This variant is also observed 20/97234 (0.02%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). The A901T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function.
Ambry Genetics RCV000619580 SCV000737765 likely benign Cardiovascular phenotype 2019-01-17 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Illumina Clinical Services Laboratory,Illumina RCV001118937 SCV001277258 benign Sick sinus syndrome 2, autosomal dominant 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

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