ClinVar Miner

Submissions for variant NM_022089.4(ATP13A2):c.2097del (p.Ser700fs)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Progenie Molecular RCV004556871 SCV004171055 pathogenic Autosomal recessive spastic paraplegia type 78 2024-09-27 criteria provided, single submitter clinical testing NM_022089.4:c.2097delC variant was identified in a patient diagnosed with hereditary spastic paraplegia, in compound heterozygosis with NM_022089.4:c.649G>A. These two variants were detected in the proband and two affected siblings, whereas 14 close relatives (2 other siblings and 14 children/grandchildren), carrying only one or none of the mutations, were unaffected. In silico analysis predicted that the c.2097delC is probably deleterious, causing a frameshift that generates a premature stop codon, which is expected to cause nonsense-mediated mRNA decay and absence of the protein. Null effect of the ATP13A2 gene is a known cause of the disease. The variant was absent in gnomAD, 1000 Genomes and European Variation Archive. In summary, we consider the c.2097delC variant to be pathogenic, as it meets the ACMG-AMP PVS1, PM2 and PP1 criteria.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004701061 SCV005203126 pathogenic Neurodegeneration with brain iron accumulation 2024-07-30 criteria provided, single submitter clinical testing Variant summary: ATP13A2 c.2097delC (p.Ser700AlafsX8) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 250412 control chromosomes. To our knowledge, no occurrence of c.2097delC in individuals affected with Neurodegeneration With Brain Iron Accumulation/Autosomal Recessive Kufor-Rakeb syndrome/AR-Spastic paraplegia 78, and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 2663862). Based on the evidence outlined above, the variant was classified as pathogenic.

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