ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.7668G>C (p.Arg2556Ser)

gnomAD frequency: 0.00001  dbSNP: rs876659035
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000215768 SCV000275004 uncertain significance Hereditary cancer-predisposing syndrome 2015-04-08 criteria provided, single submitter clinical testing The p.R2556S variant (also known as c.7668G>C), located in coding exon 52 of the NF1 gene, results from a G to C substitution at nucleotide position 7668. The arginine at codon 2556 is replaced by serine, an amino acid with dissimilar 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 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.003% (greater than 30000 alleles 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.R2556S remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV002519681 SCV002976986 uncertain significance Neurofibromatosis, type 1 2024-03-30 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 2535 of the NF1 protein (p.Arg2535Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 231226). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NF1 protein function with a negative predictive value of 95%. 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.
Ambry Genetics RCV004558508 SCV005048449 uncertain significance Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2022-04-26 criteria provided, single submitter clinical testing The c.7605G>C (p.R2535S) alteration is located in exon 51 (coding exon 51) of the NF1 gene. This alteration results from a G to C substitution at nucleotide position 7605, causing the arginine (R) at amino acid position 2535 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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