ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.1894T>A (p.Cys632Ser)

gnomAD frequency: 0.00005  dbSNP: rs370789267
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Total submissions: 10
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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 likely benign Neurofibromatosis, type 1 2024-01-28 criteria provided, single submitter clinical testing
Athena Diagnostics RCV000712402 SCV000842884 uncertain significance not provided 2018-03-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000121630 SCV000917881 uncertain significance not specified 2021-03-19 criteria provided, single submitter clinical testing Variant summary: NF1 c.1894T>A (p.Cys632Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251898 control chromosomes (gnomAD and publication data). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1894T>A in individuals affected with Neurofibromatosis Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. One co-occurrence with another pathogenic variant has been reported internally (MSH6 c.3920_3923dupATCT, p.P1309fs*11), providing supporting evidence for a benign role. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics RCV000234708 SCV001482852 uncertain significance Neurofibromatosis, type 1 2019-03-22 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx RCV000712402 SCV001811698 likely benign not provided 2023-04-25 criteria provided, single submitter clinical testing See Variant Classification Assertion Criteria.
Sema4, Sema4 RCV000220588 SCV002527426 uncertain significance Hereditary cancer-predisposing syndrome 2022-03-10 criteria provided, single submitter curation
Genome-Nilou Lab RCV000234708 SCV002561958 uncertain significance Neurofibromatosis, type 1 2022-03-15 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002483222 SCV002789985 uncertain significance Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis 2021-11-10 criteria provided, single submitter clinical testing
ITMI RCV000121630 SCV000085828 not provided not specified 2013-09-19 no assertion provided reference population

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