Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Illumina Laboratory Services, |
RCV001097110 | SCV001253364 | uncertain significance | Desmosterolosis | 2017-04-27 | 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. |
Invitae | RCV001358292 | SCV002317047 | uncertain significance | not provided | 2022-09-13 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 206 of the DHCR24 protein (p.Glu206Lys). This variant is present in population databases (rs150688144, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with DHCR24-related conditions. ClinVar contains an entry for this variant (Variation ID: 874282). 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 DHCR24 protein function. 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. |
Ambry Genetics | RCV002554906 | SCV003539494 | likely benign | Inborn genetic diseases | 2022-08-22 | criteria provided, single submitter | clinical testing | This alteration is classified as likely 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. |
Department of Pathology and Laboratory Medicine, |
RCV001358292 | SCV001553985 | uncertain significance | not provided | no assertion criteria provided | clinical testing | The DHCR24 p.Glu206Lys variant was not identified in the literature nor was it identified in ClinVar. The variant was identified in dbSNP (ID: rs150688144) and LOVD 3.0 (classified as a VUS). The variant was identified in control databases in 171 of 281752 chromosomes at a frequency of 0.0006069 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 128 of 128102 chromosomes (freq: 0.000999), African in 22 of 24956 chromosomes (freq: 0.000882), Other in 3 of 7218 chromosomes (freq: 0.000416), Latino in 14 of 35428 chromosomes (freq: 0.000395), East Asian in 3 of 19952 chromosomes (freq: 0.00015) and European (Finnish) in 1 of 25116 chromosomes (freq: 0.00004), but was not observed in the Ashkenazi Jewish or South Asian populations. The p.Glu206 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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. |