ClinVar Miner

Submissions for variant NM_001166114.2(PNPLA6):c.3518G>A (p.Arg1173Gln)

gnomAD frequency: 0.00001  dbSNP: rs1057517802
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413765 SCV000490735 likely pathogenic not provided 2016-03-14 criteria provided, single submitter clinical testing The R1135Q variant in the PNPLA6 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R1135Q variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R1135Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The R1135Q variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Invitae RCV000696127 SCV000824675 pathogenic Hereditary spastic paraplegia 39 2023-03-26 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. 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 expected to disrupt PNPLA6 protein function. ClinVar contains an entry for this variant (Variation ID: 372471). This variant is also known as p.Arg1183Gln. This missense change has been observed in individual(s) with hereditary spastic paraplegia (PMID: 31135245, 31712030). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1135 of the PNPLA6 protein (p.Arg1135Gln).
Ocular Genomics Institute, Massachusetts Eye and Ear RCV001376230 SCV001573301 uncertain significance Rod-cone dystrophy 2021-04-08 criteria provided, single submitter research The PNPLA6 c.3404G>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2. Based on this evidence we have classified this variant as Variant of Uncertain Significance.
3billion RCV000696127 SCV002573216 likely pathogenic Hereditary spastic paraplegia 39 2022-09-01 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Missense changes are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PNPLA6-related disorder (ClinVar ID: VCV000372471 / PMID: 31135245). However, the evidence of pathogenicity is insufficient at this time. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 31135245). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

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