Submissions for variant NM_001042492.3(NF1):c.584A>G (p.Lys195Arg)

gnomAD frequency: 0.00001  dbSNP: rs587778552

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166667	SCV000217472	uncertain significance	Hereditary cancer-predisposing syndrome	2016-01-14	criteria provided, single submitter	clinical testing	The p.K195R variant (also known as c.584A>G), located in coding exon 5 of the NF1 gene, results from an A to G substitution at nucleotide position 584. The lysine at codon 195 is replaced by arginine, an amino acid with highly similar properties. This alteration was reported with an allele frequency of 0.007in a cohort of 681 healthy individuals undergoing whole genome sequencing (Bodian et al.PLoS ONE; 9(4):e94554).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 6500 samples (13000 alleles) with coverage at this position.<span style="background-color:initial">To date, this alteration has been detected with an allele frequency of approximately 0.005% (greater than 110000 alleles tested) in our clinical cohort.<span style="background-color:initial">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.<span style="background-color:initial">Since supporting evidence is limited at this time, the clinical significance of<span style="background-color:initial">p.K195R<span style="background-color:initial">remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000691511	SCV000819294	uncertain significance	Neurofibromatosis, type 1	2024-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 195 of the NF1 protein (p.Lys195Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with personal or family history of breast and/or ovarian cancer (PMID: 31159747). ClinVar contains an entry for this variant (Variation ID: 134888). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
GeneKor MSA	RCV000166667	SCV000822099	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000691511	SCV001367190	uncertain significance	Neurofibromatosis, type 1	2019-03-01	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM1,BP4.
GeneDx	RCV001762266	SCV002008386	uncertain significance	not provided	2021-05-19	criteria provided, single submitter	clinical testing	Observed in individuals referred for hereditary cancer genetic testing (Tsaousis et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31159747, 24728327)
Genome-Nilou Lab	RCV000691511	SCV002561485	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Medical Genetics, University of Parma	RCV000691511	SCV002567758	likely benign	Neurofibromatosis, type 1	2022-08-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004558315	SCV005048390	likely benign	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-04-27	criteria provided, single submitter	clinical testing	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.
ITMI	RCV000121637	SCV000085835	not provided	not specified	2013-09-19	no assertion provided	reference population