ClinVar Genomic variation as it relates to human health

This variant is denoted NF1 c.5843A>T at the cDNA level, p.Gln1948Leu (Q1948L) at the protein level, and results in the change of a Glutamine to a Leucine (CAA>CTA). This variant was observed in one individual undergoing whole exome sequencing, for whom no specific clinical information was provided (Li 2017). NF1 Gln1948Leu was observed at an allele frequency of 0.08% (20/24,020) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether NF1 Gln1948Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

​<span style="background-color:initial">Thep.Q1969L<span style="background-color:initial"> variant (also known as c.5906A>T), located in coding exon 40 of theNF1<span style="background-color:initial"> gene, results from an A to T substitution at nucleotide position 5906. The glutamine at codon 1969 is replaced by leucine, an amino acid with dissimilar properties. This variant was previously reported in the SNPDatabase as rs143502927. Based on data from the NHLBI Exome Sequencing Project (ESP), the T allele has an overall frequency of approximately 0.03% (4/13006) total alleles studied, having been observed in 0.09% (4/4406) African American alleles. This variant was not reported in the 1000 Genomes Project population-based cohort. To date, this alteration has been detected with an allele frequency of approximately 0.013% (greater than 110000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be benign and tolerated by PolyPhen and SIFTin silico<span style="background-color:initial"> analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of p.Q1969L remains unclear.

DNA sequence analysis of the NF1 gene demonstrated a sequence change, c.5843A>T, in exon 39 that results in an amino acid change, p.Gln1948Leu. This sequence change does not appear to have been previously described in patients with NF1-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.084% in the African/African American subpopulation (dbSNP rs143502927). The p.Gln1948Leu change affects a moderately conserved amino acid residue located in a domain of the NF1 protein that is known to be functional. The p.Gln1948Leu substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to the lack of functional studies, the clinical significance of the p.Gln1948Leu change remains unknown at this time.

Variant summary: NF1 c.5843A>T (p.Gln1948Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251356 control chromosomes, predominantly at a frequency of 0.00074 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in NF1 causing Neurofibromatosis Type 1 phenotype (0.00021), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Although a pseudogene is present, this region does not have high homology to the pseudogene. p. c.5843A>T has been reported in the literature in an individual with Breast cancer (Guindalini_2022) without strong evidence for causality. This report does not provide unequivocal conclusions about association of the variant with Neurofibromatosis Type 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27069254, 10678181, 23460398, 29872168, 35264596, 29089047). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=5) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign.

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.