Submissions for variant NM_052859.4(RFT1):c.1133A>G (p.Tyr378Cys)

gnomAD frequency: 0.00046  dbSNP: rs143232904

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000202827	SCV000258227	uncertain significance	not specified	2015-06-17	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000765751	SCV000445561	uncertain significance	RFT1-congenital disorder of glycosylation	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Fulgent Genetics, Fulgent Genetics	RCV000765751	SCV000897135	uncertain significance	RFT1-congenital disorder of glycosylation	2022-02-10	criteria provided, single submitter	clinical testing
Invitae	RCV000765751	SCV001559818	uncertain significance	RFT1-congenital disorder of glycosylation	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 378 of the RFT1 protein (p.Tyr378Cys). This variant is present in population databases (rs143232904, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autism spectrum disorder (PMID: 33023636). ClinVar contains an entry for this variant (Variation ID: 218826). 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 RFT1 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.
Ambry Genetics	RCV002515509	SCV003691432	uncertain significance	Inborn genetic diseases	2021-11-19	criteria provided, single submitter	clinical testing	The c.1133A>G (p.Y378C) alteration is located in exon 11 (coding exon 11) of the RFT1 gene. This alteration results from a A to G substitution at nucleotide position 1133, causing the tyrosine (Y) at amino acid position 378 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.