Submissions for variant NM_001148.6(ANK2):c.9703C>T (p.Pro3235Ser)

gnomAD frequency: 0.00002  dbSNP: rs202098889

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192820	SCV001361184	uncertain significance	not specified	2019-10-08	criteria provided, single submitter	clinical testing	Variant summary: ANK2 c.9703C>T (p.Pro3235Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250650 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.9703C>T in individuals affected with Arrhythmia and no experimental evidence demonstrating an impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001205686	SCV001376955	uncertain significance	Long QT syndrome	2019-11-04	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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with ANK2-related conditions. This variant is present in population databases (rs202098889, ExAC 0.02%). This sequence change replaces proline with serine at codon 3235 of the ANK2 protein (p.Pro3235Ser). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and serine.
Ambry Genetics	RCV002375119	SCV002692194	likely benign	Cardiovascular phenotype	2020-12-09	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.