Submissions for variant NM_022089.4(ATP13A2):c.943G>A (p.Gly315Arg)

gnomAD frequency: 0.00005  dbSNP: rs150519745

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV000191065	SCV000245455	likely pathogenic	Kufor-Rakeb syndrome	2013-01-29	criteria provided, single submitter	clinical testing	Likely pathogenicity based on finding it in an individual with another deleterious variant in the gene (c.348-9_351del13; parents unavailable to determine phase). Found in a 54-year-old male with seizures, apraxia, progressive cognitive problems, confusion, speech difficulty, history of stroke.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002514094	SCV002934829	uncertain significance	Kufor-Rakeb syndrome; Autosomal recessive spastic paraplegia type 78	2024-03-25	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 315 of the ATP13A2 protein (p.Gly315Arg). This variant is present in population databases (rs150519745, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with ATP13A2-related conditions. ClinVar contains an entry for this variant (Variation ID: 209136). 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 expected to disrupt ATP13A2 protein function with a positive predictive value of 80%. 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	RCV004782296	SCV005394563	uncertain significance	not specified	2024-09-12	criteria provided, single submitter	clinical testing	Variant summary: ATP13A2 c.943G>A (p.Gly315Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 249268 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATP13A2 causing Neurodegeneration With Brain Iron Accumulation (4.8e-05 vs 0.00019), allowing no conclusion about variant significance. c.943G>A has been reported in the literature in the presumed compound heterozygous state in at least 1 individual affected with clinical features of ATP13A2-related conditions (example, Kumar_2022). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 36065636). ClinVar contains an entry for this variant (Variation ID: 209136). Based on the evidence outlined above, the variant was classified as uncertain significance.