ClinVar Miner

Submissions for variant NM_003560.4(PLA2G6):c.2370T>G (p.Tyr790Ter) (rs121908680)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000147321 SCV000194694 pathogenic Iron accumulation in brain 2014-03-17 criteria provided, single submitter clinical testing
GeneDx RCV000323935 SCV000329472 pathogenic not provided 2021-03-30 criteria provided, single submitter clinical testing Functional studies demonstrate that this variant significantly impairs catalytic activity of the PLA2G6 protein (Engel et al., 2010); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 17 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 18359254, 20886109, 16783378, 27378808, 28600779, 24800972, 18443314, 24847269, 18570303, 24745848, 30537300, 30340910, 20619503, 33101984, 31589614)
Ambry Genetics RCV000623021 SCV000741629 pathogenic Inborn genetic diseases 2016-06-20 criteria provided, single submitter clinical testing
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000006572 SCV000746537 likely pathogenic Infantile neuroaxonal dystrophy 2017-12-03 criteria provided, single submitter clinical testing
Baylor Genetics RCV000006572 SCV000807614 pathogenic Infantile neuroaxonal dystrophy 2017-09-01 criteria provided, single submitter clinical testing This variant has been previously reported as disease-causing and was found twice in our laboratory with another variant in affected individuals: a 2-year-old male with regression, hearing loss, hypotonia, failure to thrive, cerebellar atrophy, vision loss; a 5-year-old female with regression, dystonia, epilepsy, microcephaly, failure to thrive, cerebellar atrophy. Heterozygotes would be expected to be asymptomatic carriers.
Invitae RCV000006572 SCV000832045 pathogenic Infantile neuroaxonal dystrophy 2020-06-12 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the PLA2G6 gene (p.Tyr790*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 17 amino acids of the PLA2G6 protein. This variant is present in population databases (rs121908680, ExAC 0.02%). This variant as well as a different nucleotide change (c.2370_2371delTG) resulting in the same truncating effect on the PLA2G6 protein (p.Tyr790*) have been observed in the homozygous or compound heterozygous state in individuals affected with PLA2G6-related conditions (PMID: 16783378, 27378808). ClinVar contains an entry for this variant (Variation ID: 6195). Experimental studies have shown that this variant disrupts PLA2G6 enzymatic activity in vitro (PMID: 20886109). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000763481 SCV000894264 pathogenic Infantile neuroaxonal dystrophy; Neurodegeneration with brain iron accumulation 2b; Parkinson disease 14 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778661 SCV000914994 pathogenic PLA2G6-associated neurodegeneration 2018-10-18 criteria provided, single submitter clinical testing The PLA2G6 c.2370T>G (p.Tyr790Ter) variant is a stop-gained variant and has been reported in at least eight studies in a total of 11 probands with PLA2G6-associated neurodegeneration, including in at least five in a homozygous state, in five in a compound heterozygous state, and in one in a heterozygous state (Morgan et al. 2006; Carrilho et al. 2008; Gregory et al. 2008; Pinto et al. 2010; Paisan-Ruiz 2012; Illingworth et al. 2014; Blake et al. 2016; Erro et al. 2016). Of note, another variant, c.2370_2371delTG, which also results in p.Tyr790Ter, has been reported in both a homozygous and compound heterozygous state in other probands. Control data are not available for the p.Tyr790Ter variant, which is reported at a frequency of 0.000148 in the Latino from the Genome Aggregation Database. In vitro studies examining the catalytic function of the p.Tyr790Ter variant demonstrated <10% phospholipase activity compared to wildtype in the presence of two different substrates (Engel et al. 2010). Based on the collective evidence, the p.Tyr790Ter variant is classified as pathogenic for PLA2G6-associated neurodegeneration. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin RCV001250474 SCV001364070 uncertain significance Autistic disorder of childhood onset; Seizures criteria provided, single submitter clinical testing We were able to detect the known pathogenic mutation c.2370T>G in the PLA2G6 gene in the patient in a heterozygous state. The variant was also detected in the mother of the patient in heterozygous state. The PLA2G6 gene codes for phospholipase A2 of group 6 (MIM *603604). Biallelic pathogenic sequence variants in PLA2G6 have been described with three clinical manifestations of autosomal recessively inherited PLA2G6-associated neurodegeneration: 1) infantile neuroaxonal dystrophy (INAD, MIM: 256600), 2) neurodegeneration with iron accumulation in the brain (NBIA, MIM: 610217) and 3) PLA2G6-dependent dystonia parkinsonism (MIM: 612953). Clinical symptoms include psychomotor regression, symmetrical pyramidal trajectory signs, pronounced trunk hypotension, spastic quadriplegia, visual disturbances and dementia. The clinical course may be variable. The above variation leads to the formation of a premature stop codon and thus most likely to the premature termination of protein biosynthesis. The variant has already been reported in numerous patients in homozygous or compound-heterozygous condition (HGMD: CM063050). The sequence variant is listed in gnomAD 25x in heterozygous state and occurs in the European subpopulation with an allele frequency of 0.015%.
Centogene AG - the Rare Disease Company RCV000006572 SCV001426444 pathogenic Infantile neuroaxonal dystrophy criteria provided, single submitter clinical testing
Baylor Genetics RCV001333134 SCV001525629 pathogenic Neurodegeneration with brain iron accumulation 2b 2018-01-01 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 16783378, 27378808, 20886109]
OMIM RCV000006572 SCV000026755 pathogenic Infantile neuroaxonal dystrophy 2006-07-01 no assertion criteria provided literature only
Department of Genetics,Sultan Qaboos University Hospital, Oman RCV000006572 SCV000891660 pathogenic Infantile neuroaxonal dystrophy 2017-12-30 no assertion criteria provided curation
Institute of Human Genetics, Klinikum rechts der Isar RCV000006572 SCV001149880 pathogenic Infantile neuroaxonal dystrophy 2018-12-27 no assertion criteria provided clinical testing

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