ClinVar Miner

Submissions for variant NM_014855.3(AP5Z1):c.1132G>A (p.Gly378Arg)

gnomAD frequency: 0.00006  dbSNP: rs777093701
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000808499 SCV000948609 uncertain significance Hereditary spastic paraplegia 48 2021-12-08 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 378 of the AP5Z1 protein (p.Gly378Arg). This variant also falls at the last nucleotide of exon 9, which is part of the consensus splice site for this exon. This variant is present in population databases (rs777093701, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with AP5Z1-related conditions. ClinVar contains an entry for this variant (Variation ID: 652848). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Athena Diagnostics RCV001664426 SCV001880462 uncertain significance not provided 2021-04-07 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV001849111 SCV002106127 uncertain significance Hereditary spastic paraplegia 2021-04-01 criteria provided, single submitter clinical testing
Department of Biochemistry, Faculty of Medicine, University of Khartoum RCV000808499 SCV002573711 likely pathogenic Hereditary spastic paraplegia 48 criteria provided, single submitter research
Mayo Clinic Laboratories, Mayo Clinic RCV001664426 SCV004223981 uncertain significance not provided 2022-02-11 criteria provided, single submitter clinical testing PM2
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000808499 SCV005399885 uncertain significance Hereditary spastic paraplegia 48 2024-10-08 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with spastic paraplegia 48, autosomal recessive (MIM#613647). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0212 - Non-canonical splice site variant without proven consequence on splicing (no functional evidence available). This variant affects the last nucleotide of exon 9 and is also predicted to result in a missense change from glycine to arginine. (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (23 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (4 heterozygotes, 0 homozygotes). (I) 0506 - Abnormal splicing is not predicted and nucleotide is highly conserved. As a missense variant, it has conflicting in silico predictions and uninformative conservation. (I) 0705 - No comparable splice site variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been classified as a VUS by multiple clinical laboratories in ClinVar. It has also been observed in the literature as homozygous in an individual and heterozygous in their sibling, both with developmental delay and spastic limbs (PMID: 37012327). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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