Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000634962 | SCV000756338 | pathogenic | Infantile neuroaxonal dystrophy | 2023-11-20 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 479 of the PLA2G6 protein (p.His479Asp). This variant is present in population databases (no rsID available, gnomAD 0.001%). This missense change has been observed in individual(s) with clinical features of PLA2G6-related conditions (PMID: 30340910; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 529507). 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 PLA2G6 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. |
| 3billion | RCV000634962 | SCV002521897 | likely pathogenic | Infantile neuroaxonal dystrophy | 2022-05-22 | criteria provided, single submitter | clinical testing | The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.12; 3Cnet: 0.89). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PLA2G6- related disorder (ClinVar ID: VCV000529507 / PMID: 30340910). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 30340910). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. |