Submissions for variant NM_001042492.3(NF1):c.6649A>G (p.Met2217Val)

dbSNP: rs876658255

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000220275	SCV000273259	uncertain significance	Hereditary cancer-predisposing syndrome	2015-01-09	criteria provided, single submitter	clinical testing	The p.M2217V variant (also known as c.6649A>G and c.6586A>G), located in coding exon 44 of the NF1 gene, results from an A to G substitution at nucleotide position 6649. The methionine at codon 2217 is replaced by valine, 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 6501 samples (13002 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.003% (greater than 30000alleles 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 p.M2217V remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001214304	SCV001385979	uncertain significance	Neurofibromatosis, type 1	2019-11-12	criteria provided, single submitter	clinical testing	This sequence change replaces methionine with valine at codon 2196 of the NF1 protein (p.Met2196Val). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and valine. This variant has not been reported in the literature in individuals with NF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 229892). This variant is not present in population databases (ExAC no frequency). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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	RCV001214304	SCV002560978	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004558473	SCV005048322	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2021-10-25	criteria provided, single submitter	clinical testing	The c.6586A>G (p.M2196V) alteration is located in exon 43 (coding exon 43) of the NF1 gene. This alteration results from a A to G substitution at nucleotide position 6586, causing the methionine (M) at amino acid position 2196 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.