Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV004247390 | SCV003858654 | uncertain significance | Primary ciliary dyskinesia | 2023-03-03 | criteria provided, single submitter | clinical testing | The p.R757T variant (also known as c.2270G>C), located in coding exon 17 of the OFD1 gene, results from a G to C substitution at nucleotide position 2270. The arginine at codon 757 is replaced by threonine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Labcorp Genetics |
RCV003778951 | SCV004580793 | uncertain significance | Familial aplasia of the vermis; Orofaciodigital syndrome I | 2024-04-03 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 757 of the OFD1 protein (p.Arg757Thr). This variant is present in population databases (no rsID available, gnomAD 0.001%). This variant has not been reported in the literature in individuals affected with OFD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 2447627). 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 OFD1 protein function with a negative predictive value of 80%. 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. |
| Victorian Clinical Genetics Services, |
RCV004786883 | SCV005400224 | uncertain significance | Joubert syndrome 10 | 2023-07-17 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Joubert syndrome 10 (MIM#300804), Simpson-Golabi-Behmel syndrome, type 2 (MIM#300209) and Orofaciodigital syndrome I (MIM#311200). The mechanism of retinitis pigmentosa 23, (MIM#300424) is unclear. (I) 0108 - This gene is associated with both recessive and dominant disease. Most conditions associated with this gene are X-linked recessive, however orofaciodigital syndrome I (MIM#311200) is X-linked dominant. (I) 0115 - Variants in this gene are known to have variable expressivity. The same variants have been associated with several OFD1-related conditions and are known to have intra- and interfamilial variability (PMIDs: 31373179; 23033313). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to threonine. (I) 0253 - This variant is hemizygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (1 heterozygote, 0 homozygotes, 0 hemizygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |