Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Laboratory Services, |
RCV000282863 | SCV000390914 | uncertain significance | Microcephaly 4, primary, autosomal recessive | 2018-01-13 | criteria provided, single submitter | clinical testing | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. |
| Gene |
RCV000908421 | SCV000569393 | likely benign | not provided | 2018-12-14 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000908421 | SCV001053182 | likely benign | not provided | 2018-06-29 | criteria provided, single submitter | clinical testing | |
| Department of Pathology and Laboratory Medicine, |
RCV000908421 | SCV001549278 | likely benign | not provided | no assertion criteria provided | clinical testing | The KNL1 p.Thr297Ser variant was not identified in the literature but was identified in dbSNP (ID: rs201037775), LOVD 3.0 and ClinVar (classified as uncertain significance by Illumina and GeneDX, and as likely benign by Invitae). The variant was identified in control databases in 117 of 279546 chromosomes at a frequency of 0.0004185 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: African in 101 of 24148 chromosomes (freq: 0.004183), Latino in 9 of 34990 chromosomes (freq: 0.000257), Other in 1 of 7082 chromosomes (freq: 0.000141) and European (non-Finnish) in 6 of 128134 chromosomes (freq: 0.000047), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), and South Asian populations. The p.Thr297 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign. |