Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV001266643 | SCV001444819 | likely pathogenic | Inborn genetic diseases | 2018-08-23 | criteria provided, single submitter | clinical testing | |
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, |
RCV001644963 | SCV001519163 | likely pathogenic | Infantile neuroaxonal dystrophy | 2021-07-12 | criteria provided, single submitter | research | |
Invitae | RCV001644963 | SCV002312341 | likely pathogenic | Infantile neuroaxonal dystrophy | 2023-11-24 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 371 of the PLA2G6 protein (p.Val371Met). This variant is present in population databases (rs765156550, gnomAD 0.0009%). This missense change has been observed in individual(s) with infantile neuroaxonal dystrophy (PMID: 19138334, 34272103, 34445196). 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: 985636). 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 expected to disrupt PLA2G6 protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
Broad Center for Mendelian Genomics, |
RCV002537691 | SCV003761004 | likely pathogenic | PLA2G6-associated neurodegeneration | 2023-01-24 | criteria provided, single submitter | curation | The p.Val371Met variant in PLA2G6 has been reported in 4 individuals with PLA2G6-associated neurodegeneration (PMID: 34272103, 19138334, Lissens_2008, 34445196) and has been identified in 0.0009% (1/113748) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs765156550). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of the 2 affected individuals, 2 of those were homozygotes and 1 was compound heterozygote that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Val371Met variant is pathogenic (PMID: 34272103, 19138334, Lissens_2008). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive PLA2G6-associated neurodegeneration. ACMG/AMP Criteria applied: PM3_strong, PM2 (Richards 2015). |