Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000195936 | SCV000253544 | likely benign | Primary ciliary dyskinesia | 2024-01-12 | criteria provided, single submitter | clinical testing | |
| Illumina Laboratory Services, |
RCV001094485 | SCV000407197 | uncertain significance | Primary ciliary dyskinesia 15 | 2018-01-12 | 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. |
| Ambry Genetics | RCV000195936 | SCV002723681 | likely benign | Primary ciliary dyskinesia | 2021-10-04 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: 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, |
RCV001357838 | SCV001553426 | likely benign | not provided | no assertion criteria provided | clinical testing | The CCDC40 p.Asp673Asn variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs115850223), ClinVar (classified as likely benign by Invitae and as a VUS by Illumina Clinical Services for ciliary dyskinesia) and in LOVD 3.0 (classified as likely benign). The variant was also identified in control databases in 258 of 280770 chromosomes at a frequency of 0.000919 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 215 of 24180 chromosomes (freq: 0.008892), Latino in 31 of 35360 chromosomes (freq: 0.000877), Other in 2 of 7146 chromosomes (freq: 0.00028), European (non-Finnish) in 9 of 128602 chromosomes (freq: 0.00007) and South Asian in 1 of 30594 chromosomes (freq: 0.000033), while the variant was not observed in the Ashkenazi Jewish, East Asian or European (Finnish) populations. The variant occurs outside of the splicing consensus sequence however in silico or computational prediction software programs, (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing and the creation of a new 5' splice site. The p.Asp673 residue is not conserved in mammals however 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. 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. |