Submissions for variant NM_001166114.2(PNPLA6):c.4046G>A (p.Arg1349Gln)

gnomAD frequency: 0.00001  dbSNP: rs368661376

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001386441	SCV001586664	pathogenic	Hereditary spastic paraplegia 39	2022-07-06	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg1311 amino acid residue in PNPLA6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25033069, 25359264). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1073450). This missense change has been observed in individual(s) with Boucher-Neuhäuser syndrome (PMID: 27866050). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1311 of the PNPLA6 protein (p.Arg1311Gln).
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847254	SCV002105529	likely pathogenic	Hereditary spastic paraplegia	2021-12-13	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV003482369	SCV004229877	uncertain significance	not provided	2023-06-14	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). This variant appears to be associated with disease in at least one family. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. In some published literature, this variant is referred to as Arg1311Gln. Computational tools disagree on the variant's effect on normal protein function.