Submissions for variant NM_003560.4(PLA2G6):c.2246G>C (p.Trp749Ser)

dbSNP: rs587784351

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000147318	SCV000194691	likely pathogenic	Iron accumulation in brain	2013-02-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000489829	SCV000577841	likely pathogenic	not provided	2015-04-10	criteria provided, single submitter	clinical testing	The W749S variant in the PLA2G6 gene has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The W749S variant was not observed in approximately 6,350 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The W749S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, numerous missense variants in nearby residues (R741Q; R741W; R745W; R745P; R747W; E751K; G754V) have been reported in the Human Gene Mutation Database in association with PLA2G6-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. The W749S variant is a strong candidate for a disease-causing variant however, the possibility it may be a rare benign variant cannot be excluded
Invitae	RCV001849997	SCV002290958	uncertain significance	Infantile neuroaxonal dystrophy	2022-02-02	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 159763). This variant has not been reported in the literature in individuals affected with PLA2G6-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 749 of the PLA2G6 protein (p.Trp749Ser).