Submissions for variant NM_000702.4(ATP1A2):c.205G>A (p.Val69Ile)

gnomAD frequency: 0.00004  dbSNP: rs558323868

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000429547	SCV000521645	uncertain significance	not provided	2016-06-23	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the ATP1A2 gene. The V69I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project and was not observed with any significant frequency in the 1000 Genomes Project. The V69I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species. Additionally, in silico analysis predicts this variant likely does not alter the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001062407	SCV001227204	uncertain significance	Familial hemiplegic migraine	2024-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 69 of the ATP1A2 protein (p.Val69Ile). This variant is present in population databases (rs558323868, gnomAD 0.009%). This missense change has been observed in individual(s) with developmental delay and autism (PMID: 33057194, 35982159). This variant is also known as g.160093030G>A. ClinVar contains an entry for this variant (Variation ID: 381935). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ATP1A2 protein function with a negative predictive value of 95%. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003993956	SCV004813687	uncertain significance	not specified	2024-02-23	criteria provided, single submitter	clinical testing	Variant summary: ATP1A2 c.205G>A (p.Val69Ile) results in a conservative amino acid change located in the Cation-transporting P-type ATPase, N-terminal domain (IPR004014) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.5e-05 in 1614180 control chromosomes (gnomAD). c.205G>A has been reported in the literature in at-least one individual affected with autism (example: Kaplanis_2020, and Zhou_2022) . These report(s) do not provide unequivocal conclusions about association of the variant with Alternating Hemiplegia Of Childhood 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33057194, 35982159). ClinVar contains an entry for this variant (Variation ID: 381935). Based on the evidence outlined above, the variant was classified as uncertain significance.
Breakthrough Genomics, Breakthrough Genomics	RCV000429547	SCV005186999	uncertain significance	not provided		criteria provided, single submitter	not provided