Submissions for variant NM_001042492.3(NF1):c.4813A>G (p.Ile1605Val)

gnomAD frequency: 0.00001  dbSNP: rs199474766

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000213560	SCV000275324	uncertain significance	Hereditary cancer-predisposing syndrome	2015-04-24	criteria provided, single submitter	clinical testing	The p.I1605V variant (also known as c.4813A>G), located in coding exon 36 of the NF1 gene, results from an A to G substitution at nucleotide position 4813. The isoleucine at codon 1605 is replaced by valine, an amino acid with highly similar properties. This alteration has been identified in 1 of 500 individuals with neurofibromatosis type 1 (Fahsold R, et al. Am. J. Hum. Genet. 2000 Mar; 66(3):790-818). However, in one study evaluating functional and structural elements of alterations located within the lipid binding SEC14 domain, this alteration was found to have lipid binding ability, protein stability levels, and structure all comparable to wild type (Welti S, et al. Hum. Mutat. 2011 Feb; 32(2):191-7). This variant was previously reported in the SNPDatabase as rs199474766, but was absent from population-based cohorts in the NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project databases. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 55000 alleles tested) in our clinical cohort. Based on protein sequence alignment, this amino acid position is highly conserved through mammals, but valine is the reference amino acid in available lower vertebrates. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of p.I1605V remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000457745	SCV000541973	benign	Neurofibromatosis, type 1	2024-10-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000059207	SCV000808272	uncertain significance	not provided	2021-03-03	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual meeting diagnostic criteria for Neurofibromatosis type 1 (Fahsold 2000); Published functional studies are inconclusive: variant shown to be similar to wildtype with respect to protein expression, stability, and folding, but it was also shown to result in reduced lipid binding activity (Welti 2011); This variant is associated with the following publications: (PMID: 10712197, 21089070, 30104198)
Gharavi Laboratory, Columbia University	RCV000059207	SCV000920693	uncertain significance	not provided	2018-09-16	criteria provided, single submitter	research
Mendelics	RCV000457745	SCV001140372	uncertain significance	Neurofibromatosis, type 1	2019-05-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000213560	SCV002527586	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-10	criteria provided, single submitter	curation
Genome-Nilou Lab	RCV000457745	SCV002560470	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460654	SCV004198255	uncertain significance	Juvenile myelomonocytic leukemia	2023-10-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004558298	SCV005048149	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-02-15	criteria provided, single submitter	clinical testing	The c.4750A>G (p.I1584V) alteration is located in exon 35 (coding exon 35) of the NF1 gene. This alteration results from a A to G substitution at nucleotide position 4750, causing the isoleucine (I) at amino acid position 1584 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
UniProtKB/Swiss-Prot	RCV000059207	SCV000090736	not provided	not provided		no assertion provided	not provided
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000059207	SCV001798681	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001727558	SCV001972399	benign	not specified		no assertion criteria provided	clinical testing