ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.1894T>A (p.Cys632Ser) (rs370789267)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000220588 SCV000274138 uncertain significance Hereditary cancer-predisposing syndrome 2016-02-22 criteria provided, single submitter clinical testing The p.C632S variant (also known as c.1894T>A), located in coding exon 17 of the NF1 gene, results from a T to A substitution at nucleotide position 1894. The cysteine at codon 632 is replaced by serine, an amino acid with dissimilar properties.This alteration was previously reported in 1/681 individuals in a healthy, ancestrally diverse cohort via genome sequencing, having been detected in 1/331European individuals in this cohort (BodianDL et al.PLoSONE2014;9(4):e94554). This variant was previously reported in the SNPDatabase as rs370789267. Based on data from the NHLBI Exome Sequencing Project (ESP), the A allele has an overall frequency of approximately 0.01% (1/13006) total alleles studied, having been observed in0.01% (1/8600) European American alleles. To date, this alteration has been detected with an allele frequency of approximately 0.004% (greater than 110000 alleles tested) in our clinical cohort. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of p.C632S remains unclear.
Invitae RCV000234708 SCV000284394 uncertain significance Neurofibromatosis, type 1 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces cysteine with serine at codon 632 of the NF1 protein (p.Cys632Ser). The cysteine residue is weakly conserved and there is a moderate physicochemical difference between cysteine and serine. This variant is present in population databases (rs370789267, ExAC 0.01%). This variant has not been reported in the literature in individuals with NF1-related disease. ClinVar contains an entry for this variant (Variation ID: 134883). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Athena Diagnostics Inc RCV000712402 SCV000842884 uncertain significance not provided 2018-03-07 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000121630 SCV000917881 uncertain significance not specified 2017-12-22 criteria provided, single submitter clinical testing Variant summary: The NF1 c.1894T>A (p.Cys632Ser) variant involves the alteration of a conserved nucleotide and 3/5 in silico tools predict a damaging outcome for this variant. However, these predictions have yet to be functionally assessed. This variant was found in 8/276944 control chromosomes (gnomAD), predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.000055 (7/126484). This frequency does not exceed the estimated maximal expected allele frequency of a pathogenic NF1 variant (0.0002084). Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
ITMI RCV000121630 SCV000085828 not provided not specified 2013-09-19 no assertion provided reference population

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