ClinVar Miner

Submissions for variant NM_002234.4(KCNA5):c.852_869del (p.His284_His289del) (rs749443875)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000535914 SCV000647001 uncertain significance Atrial fibrillation, familial, 7 2017-06-29 criteria provided, single submitter clinical testing This variant, c.852_869del, results in the deletion of 6 amino acids of the KCNA5 protein (p.His284_His289del), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with a KCNA5-related disease. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acids is currently unknown. In summary, this variant has uncertain impact on KCNA5 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786332 SCV000925107 uncertain significance not provided 2017-08-02 no assertion criteria provided provider interpretation Testing was performed at Invitae. Seen at our center in a patient with ARVC. Given the weak gene-disease association, gene-phenotype mismatch, and lack of case data, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The KCNA5 gene is associated with autosomal dominant atrial fibrillation (MedGen UID: 393658). Additionally, the KCNA5 gene has preliminary evidence supporting a correlation with autosomal dominant pulmonary arterial hypertension (PAH) (PMID: 24936649). There is no established relationship with ARVC to date. The variant has not been reported in the literature (per PubMed and Google). Functional prediction algorithms are not available for this variant. The variant results in a 6 amino acid deletion but otherwise preserves integrity of the reading frame. The variant is not reported in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. However, given that this variant is a small indel, we can rely heavily on its absence since sequencing methods used in this cohort may not have detected this variant type. The average coverage at this site is 30x in genomes and 90x in exomes.

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