Submissions for variant NM_000037.4(ANK1):c.3829G>A (p.Val1277Met)

dbSNP: rs148942046

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001162797	SCV001324763	uncertain significance	Spherocytosis	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001162798	SCV001324764	likely benign	Hereditary spherocytosis type 1	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.
CeGaT Center for Human Genetics Tuebingen	RCV001815502	SCV002063185	likely benign	not provided	2023-06-01	criteria provided, single submitter	clinical testing	ANK1: BP4
Invitae	RCV001815502	SCV004319719	uncertain significance	not provided	2023-06-30	criteria provided, single submitter	clinical testing	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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ANK1 protein function. ClinVar contains an entry for this variant (Variation ID: 910772). This variant has not been reported in the literature in individuals affected with ANK1-related conditions. This variant is present in population databases (rs148942046, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1277 of the ANK1 protein (p.Val1277Met).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001162798	SCV004562113	likely benign	Hereditary spherocytosis type 1	2023-10-18	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003938535	SCV004749709	likely benign	ANK1-related condition	2022-09-29	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).