Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000166466 | SCV000217263 | uncertain significance | Hereditary cancer-predisposing syndrome | 2014-11-04 | criteria provided, single submitter | clinical testing | ​<span style="background-color: initial;">The<strong style="background-color: initial;">p.Y1678H<span style="background-color: initial;"> variant (also known as c.5032T>C), located in coding exon 37 of the<em style="background-color: initial;">NF1<span style="background-color: initial;"> gene, results from a T to C substitution at nucleotide position 5032. The tyrosine at codon 1678 is replaced by histidine, an amino acid with similar 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 0.01% (greater than 11000 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 probably damaging and deleterious by PolyPhen and SIFT<em style="background-color: initial;">in silico<span style="background-color: initial;"> analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of p.Y1678H remains unclear. |
| Labcorp Genetics |
RCV001053788 | SCV001218068 | uncertain significance | Neurofibromatosis, type 1 | 2024-07-15 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 1657 of the NF1 protein (p.Tyr1657His). 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: 186815). 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 expected to disrupt NF1 protein function with a positive predictive value of 95%. This variant disrupts the p.Tyr1657 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. |
| Genome- |
RCV001053788 | SCV002560496 | uncertain significance | Neurofibromatosis, type 1 | 2022-03-15 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV004558396 | SCV005048176 | uncertain significance | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2020-07-29 | criteria provided, single submitter | clinical testing | The c.4969T>C (p.Y1657H) alteration is located in exon 36 (coding exon 36) of the NF1 gene. This alteration results from a T to C substitution at nucleotide position 4969, causing the tyrosine (Y) at amino acid position 1657 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |
| Baylor Genetics | RCV004567304 | SCV005052291 | uncertain significance | Juvenile myelomonocytic leukemia | 2023-12-22 | criteria provided, single submitter | clinical testing |