Submissions for variant NM_003560.4(PLA2G6):c.416G>A (p.Arg139His)

gnomAD frequency: 0.00038  dbSNP: rs141825182

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000585504	SCV000576575	uncertain significance	not provided	2017-04-27	criteria provided, single submitter	clinical testing	The R139H variant in the PLA2G6 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R139H variant is observed in 60/41988 (0.14%) alleles from individuals of non-Finnish European background in the ExAC dataset, and no individuals were reported to be homozygous (Lek et al., 2016). The R139H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret R139H as a variant of uncertain significance.
CeGaT Center for Human Genetics Tuebingen	RCV000585504	SCV000693088	uncertain significance	not provided	2023-07-01	criteria provided, single submitter	clinical testing	PLA2G6: PM2, BP4
Fulgent Genetics, Fulgent Genetics	RCV000765651	SCV000896980	uncertain significance	Infantile neuroaxonal dystrophy; Neurodegeneration with brain iron accumulation 2B; Autosomal recessive Parkinson disease 14	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV001083799	SCV001006408	likely benign	Infantile neuroaxonal dystrophy	2024-02-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001150840	SCV001311933	uncertain significance	PLA2G6-associated neurodegeneration	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Mayo Clinic Laboratories, Mayo Clinic	RCV000585504	SCV004225619	uncertain significance	not provided	2023-06-09	criteria provided, single submitter	clinical testing	BP4
PreventionGenetics, part of Exact Sciences	RCV003925420	SCV004744827	likely benign	PLA2G6-related disorder	2022-03-25	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).