Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Laboratory Services, |
RCV001270739 | SCV001451487 | uncertain significance | Amelocerebrohypohidrotic syndrome | 2019-03-27 | criteria provided, single submitter | clinical testing | The ROGDI c.117G>T (p.Lys39Asn) variant is a missense variant located in close proximity to a canonical splice donor site (splice region variant). A literature search was performed for the gene, cDNA, and amino acid change. No publications were found based on this search. This variant is not found in the Genome Aggregation Database. The p.Lys39Asn variant resides in the alpha domain and is part of the N-terminal H1 helix that may is required for binding with C-terminal H6 helix. Furthermore, this variant is located in close proximity to a site of a splice donor variant which has been previously published in association with Kohlschutter-Tonz syndrome (Huckert et al. 2014). Based on the limited evidence, the p.Lys39Asn variant is classified as a variant of uncertain significance for Kohlschutter-Tonz syndrome. |
| Labcorp Genetics |
RCV001270739 | SCV002303218 | uncertain significance | Amelocerebrohypohidrotic syndrome | 2021-06-14 | criteria provided, single submitter | clinical testing | This sequence change replaces lysine with asparagine at codon 39 of the ROGDI protein (p.Lys39Asn). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant also falls at the last nucleotide of exon 2, which is part of the consensus splice site for this exon. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has not been reported in the literature in individuals with ROGDI-related conditions. ClinVar contains an entry for this variant (Variation ID: 989265). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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. |