Submissions for variant NM_003560.4(PLA2G6):c.2251G>A (p.Glu751Lys)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003050582	SCV003444451	pathogenic	Infantile neuroaxonal dystrophy	2023-04-28	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 2138447). For these reasons, this variant has been classified as Pathogenic. 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. This missense change has been observed in individuals with neurodegeneration with brain iron accumulation (PMID: 16783378, 31689548). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (no rsID available, gnomAD 0.03%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 751 of the PLA2G6 protein (p.Glu751Lys).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV003041414	SCV003761463	uncertain significance	PLA2G6-associated neurodegeneration	2023-01-24	criteria provided, single submitter	curation	The p.Glu751Lys variant in PLA2G6 has been reported in 2 individuals with PLA2G6-associated neurodegeneration (PMID: 16783378, 31689548), segregated with disease in 1 affected relative from 1 family (PMID: 31689548), and has been identified in 0.03% (1/3464) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1296348337). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. Of the 2 affected individuals, both of those were homozygotes, which increases the likelihood that the p.Glu751Lys variant is pathogenic (PMID: 16783378, 31689548). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Glu751Lys variant is uncertain. ACMG/AMP Criteria applied: PM3 (Richards 2015).
GeneDx	RCV003223766	SCV003919535	likely pathogenic	not provided	2022-10-20	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31689548, 16783378)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003324065	SCV004029823	pathogenic	Neurodegeneration with brain iron accumulation	2023-07-24	criteria provided, single submitter	clinical testing	Variant summary: PLA2G6 c.2251G>A (p.Glu751Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 159394 control chromosomes (gnomAD). c.2251G>A has been reported in the literature in multiple individuals affected with Neurodegeneration With Brain Iron Accumulation (example: Gafner_2020 and Morgan_2006). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 31689548, 18799783, 16783378). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic and likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.