Submissions for variant NM_014915.3(ANKRD26):c.3704A>T (p.Gln1235Leu)

gnomAD frequency: 0.00002  dbSNP: rs765506121

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000300271	SCV000362041	likely benign	Thrombocytopenia 2	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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Genetic Services Laboratory, University of Chicago	RCV001820867	SCV002065283	uncertain significance	not specified	2021-05-25	criteria provided, single submitter	clinical testing	DNA sequence analysis of the ANKRD26 gene demonstrated a sequence change, c.3704A>T, in exon 25 that results in an amino acid change, p.Gln1235Leu. This sequence change has been described in gnomAD with a frequency of 0.0027% in the Non-Finnish European sub-population (dbSNP rs765506121). The p.Gln1235Leu change affects a highly conserved amino acid residue located in a domain of the ANKRD26 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Gln1235Leu substitution. This sequence change does not appear to have been previously described in patients with ANKRD26-related disorder. Due to the lack of sufficient evidences, the clinical significance of the p.Gln1235Leu change remains unknown at this time.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002520580	SCV003483325	uncertain significance	not provided	2023-05-23	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 299733). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. This variant has not been reported in the literature in individuals affected with ANKRD26-related conditions. This sequence change replaces glutamine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1235 of the ANKRD26 protein (p.Gln1235Leu). This variant is present in population databases (rs765506121, gnomAD 0.003%).
Ambry Genetics	RCV004948253	SCV005444138	uncertain significance	Inborn genetic diseases	2024-11-28	criteria provided, single submitter	clinical testing	The p.Q1235L variant (also known as c.3704A>T), located in coding exon 25 of the ANKRD26 gene, results from an A to T substitution at nucleotide position 3704. The glutamine at codon 1235 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.