Submissions for variant NM_003560.4(PLA2G6):c.1186+1G>A

dbSNP: rs761815070

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000785898	SCV000924474	likely pathogenic	Infantile neuroaxonal dystrophy	2018-06-15	criteria provided, single submitter	research	The homozygous c.1186+1G>A variant was identified by our study in one individual with neurodegeneration with brain iron accumulation. This variant has been identified in the literature in one proband who was compound heterozygous for the c.1186+1G>A variant as well as the c.895-1G>A variant (Tonelli et al. 2010, PMID: 20584031). This variant has been identified in <0.01% (1/15304) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs761815070). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. The c.1186+1G>A variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the PLA2G6 gene is an established disease mechanism in autosomal recessive Neurodegeneration with Brain Iron Accumulation, and this is a loss of function variant. In summary, although additional studies are required to fully establish its pathogenicity, this variant is likely pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001310807	SCV001500748	likely pathogenic	not provided	2020-10-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001310807	SCV001875287	pathogenic	not provided	2023-10-23	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 20584031, 32404165)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000785898	SCV002232715	pathogenic	Infantile neuroaxonal dystrophy	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 8 of the PLA2G6 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs761815070, gnomAD 0.007%). Disruption of this splice site has been observed in individual(s) with clinical features of infantile neuroaxonal dystrophy (PMID: 20584031, 32404165; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 635025). Studies have shown that disruption of this splice site results in alternative splicing and introduces a premature termination codon (PMID: 20584031). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002535731	SCV003761003	pathogenic	PLA2G6-associated neurodegeneration	2023-01-24	criteria provided, single submitter	curation	The homozygous c.1186+1G>A variant in PLA2G6 was identified by our study in 1 individual with PLA2G6-associated neurodegeneration. The c.1186+1G>A variant in PLA2G6 has been reported in 1 compound heteroyzgous individual with PLA2G6-associated neurodegeneration (PMID: 20584031) and has been identified in 0.006% (1/16250) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs761815070). 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#: 437465) and has been interpreted as pathogenic or likely pathogenic by CeGaT Praxis fuer Humangenetik Tuebingen, GeneDx, Invitae, and Broad Institute Rare Disease Group (Broad Institute). This variant is located in the 3' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. Loss of function of the PLA2G6 gene is an established disease mechanism in autosomal recessive PLA2G6-associated neurodegeneration. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive PLA2G6-associated neurodegeneration. ACMG/AMP Criteria applied: PVS1, PM2_supporting, PM3_supporting (Richards 2015).
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV000785898	SCV005397326	pathogenic	Infantile neuroaxonal dystrophy	2023-02-18	criteria provided, single submitter	clinical testing	This sequence variant is a single nucleotide substitution (G>A) at the +1 position downstream of exon 8 of 17 of the PLA2G6 gene. As this variant alters a canonical splice donor site, it is expected to generate a non-functiol allele through either the expression of a truncated protein or a loss of PLA2G6 expression due to nonsense-mediated decay. Functiol data shows that the variant leads to the utilization of a cryptic splice site which incorporates 34 bp of intron 9, leading to a frameshift (PMID: 20584031). This is a previously reported variant (ClinVar) which has been observed in homozygous or compound heterozygous state in individuals with neuroaxol dystrophy (PMID: 20584031). This variant is present in 1/251368 alleles (0.0004%) in the gnomAD population database. Given the current information, we consider this variant to be pathogenic. ACMG Criteria: PP3, PS3, PVS1