ClinVar Miner

Submissions for variant NM_003560.4(PLA2G6):c.2221C>T (p.Arg741Trp)

gnomAD frequency: 0.00004  dbSNP: rs530348521
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255821 SCV000322368 pathogenic not provided 2016-07-27 criteria provided, single submitter clinical testing The R741W variant in the PLA2G6 gene has been reported previously in association with INAD when present in the homozygous state or when present with another missense variant in PLA2G6 (Morgan et al, 2006; Romani et al 2015). The R741W variant was not observed in approximately 6300 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 R741W 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 in mammals. In vitro enzyme assays demonstrated that the R741W amino acid substitution reduced PLA2G6 enzyme activity (Engel et al., 2010). We interpret R741W as a pathogenic variant.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000853336 SCV000996196 pathogenic Infantile neuroaxonal dystrophy 2018-09-24 criteria provided, single submitter clinical testing This variant has been previously reported as a compound heterozygous or homozygous change inindividuals with Infantile Neuroaxonal Dystrophy (PMID: 20886109, 25164370, 16783378). In vitro enzyme assays demonstrated that the p.Arg741Trp amino acid substitution reduced PLA2G6 enzyme activity (PMID: 20886109). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0007% (1/148108), and thus is presumed to be rare. The c.2221C>T (p.Arg741Trp) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.2221C>T (p.Arg741Trp) variant is classified as Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV000853336 SCV002155675 pathogenic Infantile neuroaxonal dystrophy 2023-12-09 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 741 of the PLA2G6 protein (p.Arg741Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with clinical features of infantile neuroaxonal dystrophy (PMID: 16783378, 25164370, 31516627). ClinVar contains an entry for this variant (Variation ID: 265448). 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 not expected to disrupt PLA2G6 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PLA2G6 function (PMID: 20886109). This variant disrupts the p.Arg741 amino acid residue in PLA2G6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18570303, 20669327, 26196026, 26668131, 27268037). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002282096 SCV002572188 pathogenic Neurodegeneration with brain iron accumulation 2022-08-02 criteria provided, single submitter clinical testing Variant summary: PLA2G6 c.2221C>T (p.Arg741Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.5e-06 in 154678 control chromosomes (gnomAD). c.2221C>T has been reported in the literature in homozygous and compound heterozygous individuals affected with infantile neuroaxonal dystrophy (INAD) (e.g. Morgan_2006, Romani_2015, Davids_2016, Darling_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, and it found that the variant protein had 10-25% the activity of wild-type PLA2GA (Engel_2010). Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV002470830 SCV002767948 pathogenic Neurodegeneration with brain iron accumulation 2B 2020-05-21 criteria provided, single submitter clinical testing A heterozygous missense variant, NM_003560.2(PLA2G6):c.2221C>T, has been identified in exon 16 of 17 of the PLA2G6 gene. The variant is predicted to result in a major amino acid change from arginine to tryptophan at position 741 of the protein (NP_003551.2(PLA2G6):p.(Arg741Trp)). The arginine residue at this position has moderate conservation (100 vertebrates, UCSC), and it is located in a missense hotspot region (Paisan-Ruiz, C. et al. (2009)). In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.0006% (1 heterozygote, 0 homozygotes). The variant has been previously described as pathogenic in multiple patients with infantile neuroaxonal dystrophy (ClinVar, Morgan, NV. et al. (2006), Romani, M. et al. (2015), Kapoor, S. et al. (2016), Al-Maawali, A. et al. (2016), Davids, M. et al. (2016)). Additionally, functional studies have shown that p.R741W leads to an inactive enzyme due to its location at the dimerization interface and also the variant causes loss of enzyme activity (Engel, LA. et al. (2010), Malley, KR. et al. (2018)). A different variant in the same codon resulting in a change to glutamine has also been shown to cause infantile neuroaxonal dystrophy (ClinVar, Paisan-Ruiz, C. et al. (2009)). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
Fulgent Genetics, Fulgent Genetics RCV002494803 SCV002790212 pathogenic Infantile neuroaxonal dystrophy; Neurodegeneration with brain iron accumulation 2B; Autosomal recessive Parkinson disease 14 2022-03-03 criteria provided, single submitter clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV002521855 SCV003761467 likely pathogenic PLA2G6-associated neurodegeneration 2023-01-24 criteria provided, single submitter curation The p.Arg741Trp variant in PLA2G6 has been reported in at least 10 individuals with PLA2G6-associated neurodegeneration (PMID: 16783378, 26668131, 31516627, 30340910, 32860008, 35122944, 25164370, 27196560, 30713958), segregated with disease in 1 affected relative from 1 family (PMID: 30713958), and has been identified in 0.004% (1/25224) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs530348521). 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#: 265448) and has been interpreted as pathogenic by GeneDx and Rady Children's Institute for Genomic Medicine (Rady Children's Hospital San Diego). Of the 10 affected individuals, 2 of those were homozygotes, which increases the likelihood that the p.Arg741Trp variant is pathogenic (PMID: 25164370, 27196560, 30713958). In vitro functional studies provide some evidence that the p.Arg741Trp variant may impact protein function (PMID: 20886109, 26668131, 35122944). However, these types of assays may not accurately represent biological function. 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, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive PLA2G6-associated neurodegeneration. ACMG/AMP Criteria applied: PM3, PS3_moderate, PP3, PM2_supporting (Richards 2015).

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