Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000221415 | SCV000274725 | uncertain significance | Hereditary cancer-predisposing syndrome | 2015-03-29 | criteria provided, single submitter | clinical testing | The p.C622Y variant (also known as c.1865G>A), located in coding exon 17 of the NF1 gene, results from a G to A substitution at nucleotide position 1865. The cysteine at codon 622 is replaced by tyrosine, an amino acid with highly 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 30000alleles tested) in our clinical cohort.This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be benign yet deleterious by PolyPhen and SIFT in silico analyses, respectively.Since supporting evidence is limited at this time, the clinical significance of p.C622Y remains unclear. |
| Labcorp Genetics |
RCV001853534 | SCV002191129 | uncertain significance | Neurofibromatosis, type 1 | 2020-12-01 | criteria provided, single submitter | clinical testing | 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. 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. This variant has not been reported in the literature in individuals with NF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 231003). This variant is present in population databases (rs535869486, ExAC 0.006%). This sequence change replaces cysteine with tyrosine at codon 622 of the NF1 protein (p.Cys622Tyr). The cysteine residue is moderately conserved and there is a large physicochemical difference between cysteine and tyrosine. |
| Genome- |
RCV001853534 | SCV002561951 | uncertain significance | Neurofibromatosis, type 1 | 2022-03-15 | criteria provided, single submitter | clinical testing | |
| Victorian Clinical Genetics Services, |
RCV001853534 | SCV002768387 | uncertain significance | Neurofibromatosis, type 1 | 2019-08-28 | criteria provided, single submitter | clinical testing | A heterozygous missense variant was identified,NM_000267.3(NF1):c.1865G>A in exon 17 of 57 of the NF1 gene. This substitution is predicted to create a major amino acid change from cysteine to tyrosine at position 622 of the protein, NP_000258.1(NF1):p.(Cys622Tyr). The cysteine at this position has low conservation (100 vertebrates, UCSC), and is not situated in a known functional domain. In silico software predictions of the pathogenicity of this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a frequency of 0.0004% (1 heterozygote) and has previously been reported as a variant of unknown significance (ClinVar). Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS). |