Submissions for variant NM_022089.4(ATP13A2):c.3405+9C>T

gnomAD frequency: 0.00051  dbSNP: rs374766933

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000768153	SCV000898532	uncertain significance	Kufor-Rakeb syndrome; Autosomal recessive spastic paraplegia type 78	2021-03-30	criteria provided, single submitter	clinical testing	ATP13A2 NM_022089.3 exon 28 c.3405+9C>T: This variant has not been reported in the literature but is present in 0.6% (232/34286) of Latino alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs374766933). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is an intronic variant with no predicted change in the amino acid sequence but may have an unknown effect on splicing. Further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Invitae	RCV000768153	SCV001016438	benign	Kufor-Rakeb syndrome; Autosomal recessive spastic paraplegia type 78	2024-01-25	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001098910	SCV001255307	uncertain significance	Kufor-Rakeb syndrome	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV001556844	SCV001778493	likely benign	not provided	2020-10-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003396334	SCV004122971	benign	not specified	2023-10-16	criteria provided, single submitter	clinical testing	Variant summary: ATP13A2 c.3405+9C>T alters a non-conserved nucleotide located at a position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0011 in 242844 control chromosomes, predominantly at a frequency of 0.0068 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 36-fold of the estimated maximal expected allele frequency for a pathogenic variant in ATP13A2 causing Neurodegeneration With Brain Iron Accumulation phenotype (0.00019), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.3405+9C>T in individuals affected with Neurodegeneration With Brain Iron Accumulation and no experimental evidence demonstrating its impact on protein function have been reported. Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as benign (n=1), likely benign (n=1), or uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as benign.
PreventionGenetics, part of Exact Sciences	RCV003975312	SCV004791016	likely benign	ATP13A2-related condition	2020-04-01	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).