Submissions for variant NM_001166114.2(PNPLA6):c.4003C>T (p.Pro1335Ser)

gnomAD frequency: 0.00005  dbSNP: rs151264767

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000470003	SCV000550414	pathogenic	Hereditary spastic paraplegia 39	2025-01-14	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1297 of the PNPLA6 protein (p.Pro1297Ser). This variant is present in population databases (rs151264767, gnomAD 0.09%). This missense change has been observed in individual(s) with clinical features of hereditary spastic paraplegia (internal data). 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. ClinVar contains an entry for this variant (Variation ID: 409994). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PNPLA6 protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV002293441	SCV002586584	likely pathogenic	not provided	2025-03-27	criteria provided, single submitter	clinical testing	Identified in two siblings with spastic paraplegia who also harbored a second missense variant in PNPLA6, however it is not known whether the variants occurred on the same (in cis) or opposite (in trans) chromosomes (PMID: 32623594); In silico analysis indicates that this missense variant does not alter protein structure/function; Also known as p.(P1335S); This variant is associated with the following publications: (PMID: 36825042, 39420034, 32623594)
Athena Diagnostics	RCV002293441	SCV004229876	uncertain significance	not provided	2023-06-19	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 higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. This variant is also referred to as c.3889C > T, p.Pro1297Ser in published literature. Computational tools disagree on the variant's effect on normal protein function.
Molecular Genetics, Royal Melbourne Hospital	RCV000470003	SCV004812376	likely pathogenic	Hereditary spastic paraplegia 39	2024-11-04	criteria provided, single submitter	clinical testing	This sequence change in PNPLA6 is predicted to replace proline with serine at codon 1335, p.(Pro1335Ser). The proline residue is moderately conserved (100 vertebrates, Multiz Alignments), and is not located in an annotated functional domain. There is a moderate physicochemical difference between proline and serine. PNPLA6, in which the variant was identified, is a gene significantly constrained for missense variation and where pathogenic missense variants are a common mechanism of disease (gnomAD v4.1). The highest population minor allele frequency in gnomAD v4.1 is 0.1% (49/29,320 alleles) in the Ashkenazi Jewish population, while the highest continental population minor allele frequency in gnomAD v4.1 is 0.002% (1/58,752 alleles) in the Admixed-American population. This variant has been detected as compound heterozygous in multiple individuals with spastic paraparesis, with at least one pathogenic variant confirmed on the second allele (PMID: 36825042, Invitae). The variant has been reported to segregate in affected family members from four families (PMID: 36825042, 32623594; Invitae). Computational evidence predicts a benign effect for the missense substitution (REVEL = 0.019) and predicts no impact on splicing (SpliceAI) for the nucleotide change. Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.7.0, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM3_Strong, PP1_Strong, PP2, BP4
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000470003	SCV005086434	likely pathogenic	Hereditary spastic paraplegia 39	2024-09-21	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Boucher-Neuhauser syndrome (MIM#215470), Oliver-McFarlane syndrome (MIM#275400) and spastic paraplegia (MIM#612020) (OMIM). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (13 heterozygotes, 0 homozygotes). (SP) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported as compound heterozygous in individuals with early-onset motor delays, including two siblings with spastic paraplegia, with one developing carbidopa-levodopa-responsive early-onset parkinsonism (J. Witt, M. Davis [abstract] Mov Disord. 2020; 35 (suppl 1); PMID: 32623594). In addition, this variant is compound heterozygous with a missense variant in an individual with spastic paraparesis and hereditary spastic paraplegia (Invitae, personal communication. However, it should also be noted that this variant has been classified as pathogenic and a VUS in ClinVar and as likely benign in a study of two brothers with levodopa-responsive parkinsonism and gait ataxia, respectively (PMID: 36825042). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1206 - This variant has been shown to be paternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
GenomeConnect - Invitae Patient Insights Network	RCV001535779	SCV001749937	not provided	Ataxia-hypogonadism-choroidal dystrophy syndrome; Laurence-Moon syndrome; Hereditary spastic paraplegia 39		no assertion provided	phenotyping only	Variant interpreted as Pathogenic 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.