rs773955314
- Pathogenic/Likely pathogenic
Your Genotype
Sign InDescription
DNA sequence analysis of the PNPLA6 gene demonstrated a sequence change, c.3241G>A, in exon 30 that results in an amino acid change, p.Gly1081Arg. This sequence change (described in the literature as c.3385G>A, p.Gly1129Arg) has been reported with a second pathogenic variant in patients clinically diagnosed with Oliver-McFarlane syndrome with features of Laurence-Moon syndrome (PMID: 25480986). A different nucleotide substitution resulting in the same amino acid change (c.3241G>C; described in the literature as c.3385G>C) has also been identified in patients with Oliver McFarlane syndrome (PMID: 25574898). The c.3241G>A sequence change has been described in the gnomAD database with a low population frequency of 0.0087% in the Latino sub-population (dbSNP rs773955314). The p.Gly1081Arg change affects a highly conserved amino acid residue located in a domain of the PNPLA6 protein that is known to be functional. The p.Gly1081Arg substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL).
This sequence change replaces glycine with arginine at codon 1081 of the PNPLA6 protein (p.Gly1081Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs773955314, ExAC 0.009%). This missense change has been observed in individuals with Oliver-McFarlane syndrome and clinical features of Laurence Moon syndrome (PMID: 25480986). This variant is also known as p.Gly1129Arg. 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 disruptive. Experimental studies have shown that this missense change affects PNPLA6 protein function (PMID: 25480986). This variant disrupts the c.3241G nucleotide in the PNPLA6 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 25574898). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Reference Allele
G
Alternative Allele
A
C
Chromosome
19
Location
7557242
Variant Type
SNP
Genes
ClinVar
Name
NM_001166114.2(PNPLA6):c.3355G>A (p.Gly1119Arg)
Allele
A
Clinical Significance
Pathogenic/Likely pathogenic