Submissions for variant NM_005765.3(ATP6AP2):c.490G>A (p.Val164Ile)

gnomAD frequency: 0.00011  dbSNP: rs142013283

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001704969	SCV000240384	likely benign	not provided	2019-12-03	criteria provided, single submitter	clinical testing
Invitae	RCV000640918	SCV000762522	uncertain significance	Syndromic X-linked intellectual disability Hedera type	2023-12-23	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 164 of the ATP6AP2 protein (p.Val164Ile). This variant is present in population databases (rs142013283, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with ATP6AP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 204912). 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 ATP6AP2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000767901	SCV000898540	uncertain significance	Syndromic X-linked intellectual disability Hedera type; X-linked parkinsonism-spasticity syndrome	2018-10-25	criteria provided, single submitter	clinical testing	ATP6AP2 NM_005765.2 exon 5 p.Val164Ile (c.490G>A): This variant has not been reported in the literature but is present in 3/27186 Latino alleles, including 1 hemizygote in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs142013283). This variant is present in ClinVar (Variation ID:204912). This variant amino acid Isoleucine (Ile) is present in >30 species and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224203	SCV003920281	uncertain significance	Syndromic X-linked intellectual disability Hedera type; X-linked parkinsonism-spasticity syndrome; Congenital disorder of glycosylation, type IIr	2021-03-30	criteria provided, single submitter	clinical testing	ATP6AP2 NM_005765 exon 5 p.Val164Ile (c.490G>A): This variant has not been reported in the literature but is present in 3/27186 Latino alleles, including 1 hemizygote in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs142013283). This variant is present in ClinVar (Variation ID:204912). This variant amino acid Isoleucine (Ile) is present in >30 species and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.