Submissions for variant NM_001042492.3(NF1):c.99A>G (p.Lys33=)

dbSNP: rs786203280

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166515	SCV000217315	uncertain significance	Hereditary cancer-predisposing syndrome	2014-10-23	criteria provided, single submitter	clinical testing	The c.99A>G variant (also known as p.K33K) located in coding exon 2, results from an A to G substitution at nucleotide position 99 of the NF1 gene. This nucleotide substitution does not change the amino acid at codon 33. 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 0.01% (greater than 11000 alleles tested) in our clinical cohort. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to create of a new alternate splice donor splice site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of c.99A>G remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000632386	SCV000753564	pathogenic	Neurofibromatosis, type 1	2023-06-04	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 186861). This variant has been observed in individual(s) with neurofibromatosis type 1 (PMID: 26740943, 31766501; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change affects codon 33 of the NF1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the NF1 protein.
Genome-Nilou Lab	RCV000632386	SCV002561405	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002381532	SCV002688940	likely pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2019-11-13	criteria provided, single submitter	clinical testing	The c.99A>G variant (also known as p.K33K), located in coding exon 2 of the NF1 gene, results from an A to G substitution at nucleotide position 99. This nucleotide substitution does not change the amino acid at codon 33. However, this change occurs in the last base pair of coding exon 2, which makes it likely to have some effect on normal mRNA splicing. This variant has been identified in multiple individuals with a clinical diagnosis or features of neurofibromatosis type 1 (Bianchessi D et al. Mol Genet Genomic Med, 2015 Nov;3:513-25; Messiaen L et al. JAMA, 2009 Nov;302:2111-8). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to create a new alternate splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.