Submissions for variant NM_003560.4(PLA2G6):c.1058C>T (p.Pro353Leu)

gnomAD frequency: 0.00004  dbSNP: rs587784326

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000147280	SCV000194653	likely pathogenic	Iron accumulation in brain	2014-05-27	criteria provided, single submitter	clinical testing
Invitae	RCV001364740	SCV001560908	uncertain significance	Infantile neuroaxonal dystrophy	2022-08-16	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 353 of the PLA2G6 protein (p.Pro353Leu). 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 individual(s) with autosomal recessive infantile neuroaxonal dystrophy (PMID: 16783378). ClinVar contains an entry for this variant (Variation ID: 159726). 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. 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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002515975	SCV003761008	uncertain significance	PLA2G6-associated neurodegeneration	2023-01-24	criteria provided, single submitter	curation	The p.Pro353Leu variant in PLA2G6 has been reported in 3 individuals with PLA2G6-associated neurodegeneration (PMID: 16783378, 29859652, 31493945) and has been identified in 0.006% (1/17520) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs587784326). 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. This variant has also been reported in ClinVar (Variation ID#: 159726) and has been interpreted as likely pathogenic by Genetic Services Laboratory (University of Chicago) and as a variant of uncertain significance by Invitae. Of the 2 affected individuals, 1 of those was a homozygote and 1 was compound heterozygote that carried a reported pathogenic variant with unknown phase, which increases the likelihood that the p.Pro353Leu variant is pathogenic (VariationID: 6195; PMID: 29859652, 31493945). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Pro353Leu variant is uncertain. ACMG/AMP Criteria applied: PM2_supporting, PM3, PP3 (Richards 2015).