ClinVar Genomic variation as it relates to human health

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.

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge

This sequence change is predicted to replace glycine with alanine at codon 890 of the PNPLA6 protein, p.(Gly890Ala). The glycine residue is highly conserved (100 vertebrates, UCSC), and located in the Patatin-like phospholipase domain in the last position of a glycine-rich loop motif predicted to be involved in nucleotide binding (Uniprot). There is a moderate physicochemical difference between glycine and alanine. The highest population minor allele frequency in gnomAD v2.1 is 0.5% (50/10,250 alleles) in the Ashkenazi population, while the highest continental population minor allele frequency in gnomAD v2.1 is 0.005% (6/127,074 alleles) in the European (non-Finnish) population. The variant has been reported as a variant of uncertain significance and likely benign (ClinVar ID: 581260), with no reports in the relevant medical literature. It is compound heterozygous with a likely pathogenic PNPLA6 variant in an individual with cerebellar ataxia, spasticity, and ophthalmoplegia (Royal Melbourne Hospital). This variant falls three nucleotides from the acceptor splice site of exon 27 of the PNPLA6 coding sequence. Multiple lines of computational evidence predict no splice defect (SpliceAI, MaxEntScan, NNSplice), and predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.5.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM3, PM2_Supporting, PP3.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as 3A-VUS. 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 glycine to alanine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 59 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated patatin-like phospholipase domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported as likely benign and a variant of uncertain significance in ClinVar. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1201 - Heterozygous variant detected in trans with a second likely pathogenic heterozygous variant (NM_001166114.1 (PNPLA6): c.4003C>T; p.(Pro1335Ser)) in a recessive disease. (SP) 1205 - This variant has been shown to be maternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

BS1, PP3