Submissions for variant NM_052859.4(RFT1):c.200G>A (p.Arg67His)

gnomAD frequency: 0.00003  dbSNP: rs753527390

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414688	SCV000491491	likely pathogenic	not provided	2016-06-08	criteria provided, single submitter	clinical testing	The R67H variant in the RFT1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R67H variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R67H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in the same residue (R67C) has been reported in association with congenital disorders of glycosylation when seen in the homozygous state and studies have shown reduced function for the R67C variant (Haeuptle et al., 2008; Vleugels et al., 2009), supporting the functional importance of this residue. The R67H variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Invitae	RCV002524642	SCV003524591	uncertain significance	RFT1-congenital disorder of glycosylation	2022-08-12	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 67 of the RFT1 protein (p.Arg67His). This variant is present in population databases (rs753527390, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with RFT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 372948). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Arg67 amino acid residue in RFT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18313027, 19267216, 30653653). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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	RCV003317204	SCV004021266	uncertain significance	not specified	2023-06-05	criteria provided, single submitter	clinical testing	Variant summary: RFT1 c.200G>A (p.Arg67His) 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 0.00012 in 251426 control chromosomes. To our knowledge, no occurrence of c.200G>A in individuals affected with RFT1-Congenital Disorder Of Glycosylation and no experimental evidence demonstrating its impact on protein function have been reported. Another change affecting the same amino acid (p.R67C) has been associated with pathogenicity in ClinVar. However the evidence is currently insufficient to determine the role of this variant in disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.