Submissions for variant NM_001042492.3(NF1):c.2671G>C (p.Val891Leu)

dbSNP: rs1060500256

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000457646	SCV000541990	uncertain significance	Neurofibromatosis, type 1	2024-11-18	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 891 of the NF1 protein (p.Val891Leu). 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: 404435). 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.
Ambry Genetics	RCV000565524	SCV000663098	uncertain significance	Hereditary cancer-predisposing syndrome	2016-02-17	criteria provided, single submitter	clinical testing	The p.V891L variant (also known as c.2671G>C), located in coding exon 21 of the NF1 gene, results from a G to C substitution at nucleotide position 2671. The valine at codon 891 is replaced by leucine, an amino acid with highly 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 110000 alleles tested) in our clinical cohort.This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive.Since supporting evidence is limited at this time, the clinical significance of this alterationremains unclear.
Genome-Nilou Lab	RCV000457646	SCV002562082	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003463844	SCV004198379	uncertain significance	Juvenile myelomonocytic leukemia	2023-08-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004559058	SCV005047661	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2021-04-05	criteria provided, single submitter	clinical testing	The c.2671G>C (p.V891L) alteration is located in exon 21 (coding exon 21) of the NF1 gene. This alteration results from a G to C substitution at nucleotide position 2671, causing the valine (V) at amino acid position 891 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.