Submissions for variant NM_003560.4(PLA2G6):c.1021G>A (p.Ala341Thr)

gnomAD frequency: 0.00001  dbSNP: rs769000561

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001268304	SCV001447133	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Laboratório de Neurologia Aplicada e Experimental, Faculdade de Medicina de Ribeirao Preto – Universidade de Sao Paulo	RCV002245911	SCV001934608	pathogenic	Infantile neuroaxonal dystrophy; Neurodegeneration with brain iron accumulation 2B	2021-07-20	criteria provided, single submitter	research	The p.Ala341Thr variant in the PLA2G6 gene has been described in compound heterozygous with another variant (p.His157Arg) in 2 brothers with infantile neuroaxonal dystrophy and brain iron accumulation (INAD) (PMID: 18799783). This variant has been observed in a homozygous state in one patient with moderate CMT2/dHMN with the onset of symptoms at five years of age. This sequence change replaces alanine with threonine at codon 341 of the PLA2G6 protein, and this amino acid residue is highly conserved in different species. This variant is in a hotspot region and an important functional domain of the protein (ankyrin repeat regions). This variant is present in heterozygous in 2 alleles in the GnomAD database and absents in the ABraOM database. ClinVar classifies this variant as Likely Pathogenic (Variation ID: 987077), 1 star (criteria provided, one submission). In summary, the p.Ala341Thr meets our criteria to be classified as pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002537707	SCV003761009	uncertain significance	PLA2G6-associated neurodegeneration	2023-01-24	criteria provided, single submitter	curation	The p.Ala341Thr variant in PLA2G6 has been reported in 3 individuals with PLA2G6-associated neurodegeneration (PMID: 18799783, 34622992, Jansen_2015, 16783378), segregated with disease in 1 affected relative from 1 family (PMID: 18799783), and has been identified in 0.003% (2/64154) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs769000561). 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#: 987077) and has been interpreted as likely pathogenic or pathogenic by Institute of Medical Genetics and Applied Genomics (University Hospital Tübingen) and Laboratório de Neurologia Aplicada e Experimental (Faculdade de Medicina de Ribeirao Preto – Universidade de Sao Paulo). Of the 3 affected individuals, 1 was a homozygote, which increases the likelihood that the p.Ala341Thr variant is pathogenic (ClinVar). In vitro functional studies provide some evidence that the p.Ala341Thr variant may slightly impact protein function (PMID: 20886109). However, these types of assays may not accurately represent biological function. 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.Ala341Thr variant is uncertain. ACMG/AMP Criteria applied: PM2_supporting, PS3_supporting, PM3_supporting (Richards 2015).