Submissions for variant NM_001166114.2(PNPLA6):c.1430C>T (p.Ser477Leu)

gnomAD frequency: 0.00004  dbSNP: rs140929996

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000687606	SCV000815183	uncertain significance	Hereditary spastic paraplegia 39	2022-08-16	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 438 of the PNPLA6 protein (p.Ser438Leu). This variant is present in population databases (rs140929996, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of PNPLA6-related conditions (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 567501). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Illumina Laboratory Services, Illumina	RCV000687606	SCV001291092	uncertain significance	Hereditary spastic paraplegia 39	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
New York Genome Center	RCV002227486	SCV002506844	uncertain significance	Ataxia-hypogonadism-choroidal dystrophy syndrome; Laurence-Moon syndrome; Hereditary spastic paraplegia 39; Trichomegaly-retina pigmentary degeneration-dwarfism syndrome	2021-07-16	criteria provided, single submitter	clinical testing	The inherited c.1430C>T (p.Ser477Leu) variant identified in the PNPLA6 gene substitutes a moderately conserved Serine for Leucine atamino acid 477/1366 (exon 12/32). This variant is found with low frequency in gnomAD(v3.1.1) (5 heterozygotes, 0 homozygotes; allele frequency: 3.29e-5) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Tolerated (SIFT; score: 0.219) and Benign (REVEL; score: 0.013) to the function of the canonical transcript. It is reported as a Variant of Uncertain Significance in ClinVar (VarID:567501) and to our current knowledge has not been reported in affected individuals in the literature. The p.Ser477 residue is not within a mapped domain of PNPLA6 (UniProtKB:Q8IY17). Given the lack of compelling evidence for its pathogenicity, the inherited c.1430C>T (p.Ser477Leu) variant identified in the PNPLA6 gene is reported as a Variant of Uncertain Significance.
Ambry Genetics	RCV004026268	SCV005007049	uncertain significance	Inborn genetic diseases	2023-02-14	criteria provided, single submitter	clinical testing	The c.1313C>T (p.S438L) alteration is located in exon 15 (coding exon 13) of the PNPLA6 gene. This alteration results from a C to T substitution at nucleotide position 1313, causing the serine (S) at amino acid position 438 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GenomeConnect - Invitae Patient Insights Network	RCV001535780	SCV001749938	not provided	Ataxia-hypogonadism-choroidal dystrophy syndrome; Laurence-Moon syndrome; Hereditary spastic paraplegia 39		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 03-03-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.