Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000414424 | SCV000490747 | likely pathogenic | not provided | 2016-05-31 | criteria provided, single submitter | clinical testing | The A99V variant in the PSAT1 gene has been reported previously in the homozygous or compound heterozygous state in multiple unrelated individuals with Neu-Laxova syndrome (Acuna-Hidalgo et al., 2014). The A99V variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A99V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. As an alternate mechanism, splice predictor models show that c.296_297delCTinsTG (A99V) creates a cryptic donor splice site, which may result in abnormal gene splicing. Based on the available information, we now interpret A99V as a strong candidate for a disease-causing mutation; however, the possibility it may be a rare benign variant cannot be excluded. |
| Invitae | RCV000819927 | SCV000960614 | pathogenic | Neu-Laxova syndrome 2 | 2024-01-22 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 99 of the PSAT1 protein (p.Ala99Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with Neu-Laxova syndrome (PMID: 25152457, 30214071, 32579715). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 372478). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PSAT1 function (PMID: 32077105). For these reasons, this variant has been classified as Pathogenic. |