ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.5257G>A (p.Val1753Ile)

gnomAD frequency: 0.00004  dbSNP: rs148540952
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130179 SCV000185016 uncertain significance Hereditary cancer-predisposing syndrome 2015-11-23 criteria provided, single submitter clinical testing The p.V1753I variant (also known as c.5257G>A), located in coding exon 37 of the NF1 gene, results from a G to A substitution at nucleotide position 5257. The valine at codon 1753 is replaced by isoleucine, an amino acid with highly similar properties. This variant was previously reported in the SNPDatabase as rs148540952. 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 in 0.02% (1/4406) African American alleles. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than110000alleles tested) in our clinical cohort.This amino acid position is completely conserved on sequence alignment. 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.V1753I remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV000205990 SCV000260517 likely benign Neurofibromatosis, type 1 2025-01-14 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001588983 SCV001474063 uncertain significance not provided 2020-03-12 criteria provided, single submitter clinical testing The NF1 c.5257G>A; p.Val1753Ile variant (rs148540952), also known as c.5194G>A; p.Val1732Ile for NM_000267, is reported in the ClinVar database (Variation ID: 141594). This variant is found in the African population with an allele frequency of 0.04% (10/24782 alleles) in the Genome Aggregation Database. The valine at codon 1753 is highly conserved, but computational analyses (SIFT: Tolerated, PolyPhen-2: Possibly Damaging) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of this variant is uncertain at this time.
GeneDx RCV001588983 SCV001816886 likely benign not provided 2020-10-08 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 29360550)
Sema4, Sema4 RCV000130179 SCV002527608 uncertain significance Hereditary cancer-predisposing syndrome 2022-02-16 criteria provided, single submitter curation
Ambry Genetics RCV003162581 SCV003895303 benign Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2023-01-11 criteria provided, single submitter clinical testing This alteration is classified as 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.

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