Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Laboratory Services, |
RCV001111819 | SCV001269420 | uncertain significance | Fraser syndrome 2 | 2017-04-28 | criteria provided, single submitter | clinical testing | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. |
| Fulgent Genetics, |
RCV002491354 | SCV002787080 | uncertain significance | Isolated cryptophthalmia; Fraser syndrome 2 | 2021-12-08 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV001358377 | SCV003282576 | uncertain significance | not provided | 2022-10-26 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 187 of the FREM2 protein (p.Pro187Leu). This variant is present in population databases (rs200691357, gnomAD 0.1%). This missense change has been observed in individual(s) with clinical features of Fraser syndrome (PMID: 24115501). ClinVar contains an entry for this variant (Variation ID: 882277). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. |
| Department of Pathology and Laboratory Medicine, |
RCV001358377 | SCV001554092 | uncertain significance | not provided | no assertion criteria provided | clinical testing | The FREM2 p.Pro187Leu variant was identified in 1 of 22 proband chromosomes (frequency: 0.045) from patients with Ablepharon macrostomia syndrome; the phenotype of the patient with this variant also included ablepharon, abnormal pinnae and microtia, deafness, macrostomia, hypoplastic scrotum and syndactyly (Schanze_2013_PMID:24115501). The variant was identified in dbSNP (ID: rs200691357) but was not identified in ClinVar. The variant was identified in control databases in 55 of 243936 chromosomes at a frequency of 0.0002255 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 11 of 9514 chromosomes (freq: 0.001156), European (non-Finnish) in 36 of 107434 chromosomes (freq: 0.000335), Other in 1 of 6466 chromosomes (freq: 0.000155), African in 3 of 21744 chromosomes (freq: 0.000138), European (Finnish) in 3 of 21928 chromosomes (freq: 0.000137) and Latino in 1 of 31746 chromosomes (freq: 0.000032), but was not observed in the East Asian or South Asian populations. The p.Pro187 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. |