Submissions for variant NM_004736.4(XPR1):c.2009G>A (p.Arg670His)

gnomAD frequency: 0.00006  dbSNP: rs142675657

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002573252	SCV003727143	uncertain significance	Inborn genetic diseases	2022-01-03	criteria provided, single submitter	clinical testing	The c.2009G>A (p.R670H) alteration is located in exon 14 (coding exon 14) of the XPR1 gene. This alteration results from a G to A substitution at nucleotide position 2009, causing the arginine (R) at amino acid position 670 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001579608	SCV004324540	uncertain significance	not provided	2024-05-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 670 of the XPR1 protein (p.Arg670His). This variant is present in population databases (rs142675657, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with XPR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1209965). 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 tolerated. 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	RCV005237919	SCV005884606	uncertain significance	not specified	2024-12-10	criteria provided, single submitter	clinical testing	Variant summary: XPR1 c.2009G>A (p.Arg670His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 251444 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in XPR1 causing Idiopathic Basal Ganglia Calcification, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.2009G>A in individuals affected with Idiopathic Basal Ganglia Calcification and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1209965). Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001579608	SCV001807882	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001579608	SCV001966264	likely benign	not provided		no assertion criteria provided	clinical testing