Submissions for variant NM_001042492.3(NF1):c.74C>T (p.Thr25Ile)

dbSNP: rs1555604874

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000573262	SCV000663094	uncertain significance	Hereditary cancer-predisposing syndrome	2016-02-23	criteria provided, single submitter	clinical testing	The p.T25I variant (also known as c.74C>T), located in coding exon 2 of the NF1 gene, results from a C to T substitution at nucleotide position 74. The threonine at codon 25 is replaced by isoleucine, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 110000alleles tested) in our clinical cohort.This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis.Since supporting evidence is limited at this time, the clinical significance of this alterationremains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001067528	SCV001232594	uncertain significance	Neurofibromatosis, type 1	2024-12-15	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 25 of the NF1 protein (p.Thr25Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 480097). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt NF1 protein function with a negative predictive value of 95%. 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.
Genome-Nilou Lab	RCV001067528	SCV002561397	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004553256	SCV004121012	uncertain significance	NF1-related disorder	2022-09-08	criteria provided, single submitter	clinical testing	The NF1 c.74C>T variant is predicted to result in the amino acid substitution p.Thr25Ile. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In ClinVar, this variant is interpreted as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/480097/?new_evidence=true). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Ambry Genetics	RCV004559228	SCV005048425	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2020-09-30	criteria provided, single submitter	clinical testing	The c.74C>T (p.T25I) alteration is located in exon 2 (coding exon 2) of the NF1 gene. This alteration results from a C to T substitution at nucleotide position 74, causing the threonine (T) at amino acid position 25 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV005000243	SCV005624657	uncertain significance	not provided	2024-02-07	criteria provided, single submitter	clinical testing