Submissions for variant NM_052859.4(RFT1):c.436C>T (p.His146Tyr)

gnomAD frequency: 0.00036  dbSNP: rs201794647

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000892833	SCV001036736	benign	RFT1-congenital disorder of glycosylation	2024-12-07	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000892833	SCV001310809	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.
Ambry Genetics	RCV002539402	SCV003679397	uncertain significance	Inborn genetic diseases	2020-10-14	criteria provided, single submitter	clinical testing	The c.436C>T (p.H146Y) alteration is located in exon 4 (coding exon 4) of the RFT1 gene. This alteration results from a C to T substitution at nucleotide position 436, causing the histidine (H) at amino acid position 146 to be replaced by a tyrosine (Y). Based on data from the Genome Aggregation Database (gnomAD) database, the RFT1 c.436C>T alteration was observed in 0.03% (89/282752) of total alleles studied, with a frequency of 0.57% (59/10366) in the Ashkenazi Jewish subpopulation. This variant was identified in an individual with intellectual disability, dysmorphic features, hyperextensible skin, and hypotonia in conjunction with a second RFT1 variant (Bruel, 2019). This amino acid position is well conserved in available vertebrate species. The p.H146Y alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003950413	SCV004762488	likely benign	RFT1-related disorder	2019-11-21	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).