Submissions for variant NM_003560.4(PLA2G6):c.2129G>A (p.Arg710His)

gnomAD frequency: 0.00010  dbSNP: rs147455037

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000454205	SCV000537970	likely pathogenic	Abnormal brain morphology		criteria provided, single submitter	research
Invitae	RCV000804046	SCV000943938	uncertain significance	Infantile neuroaxonal dystrophy	2022-09-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 710 of the PLA2G6 protein (p.Arg710His). This variant is present in population databases (rs147455037, gnomAD 0.008%). This missense change has been observed in individual(s) with features of neuroaxonal dystrophy (PMID: 26539891, 31493945). This variant is also known as p.R656H. ClinVar contains an entry for this variant (Variation ID: 402191). 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.
GeneDx	RCV001550736	SCV001771116	uncertain significance	not provided	2022-06-03	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26539891, 31493945, 34426522)
3billion	RCV000804046	SCV002059080	likely pathogenic	Infantile neuroaxonal dystrophy	2022-01-03	criteria provided, single submitter	clinical testing	The variant was co-segregated with Infantile neuroaxonal dystrophy 1 in multiple affected family members (PMID: 26539891, PP1_P). 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: 26539891, PM3_M). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000159759, PMID:26539891, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.754, 3CNET: 0.756, PP3_P). A missense variant is a common mechanism associated with Infantile neuroaxonal dystrophy 1 (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000050, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002526373	SCV003761469	uncertain significance	PLA2G6-associated neurodegeneration	2023-01-24	criteria provided, single submitter	curation	The p.Arg710His variant in PLA2G6 has been reported in 1 individual, in the homozygous state, with PLA2G6-associated neurodegeneration (PMID: 26539891) and has been identified in 0.008% (10/129094) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs147455037). 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#: 402191) and has been interpreted as likely pathogenic by Lupski Lab (Baylor-Hopkins CMG, Baylor College of Medicine), GeneDx, and 3billion, and as a variant of uncertain significance by Invitae. 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.Arg710His variant is uncertain. ACMG/AMP Criteria applied: PM3_supporting, PP3, PM2_supporting (Richards 2015).