Submissions for variant NM_020376.4(PNPLA2):c.236G>A (p.Arg79Gln)

gnomAD frequency: 0.00045  dbSNP: rs139576982

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000528874	SCV000641130	uncertain significance	Neutral lipid storage myopathy	2022-08-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 79 of the PNPLA2 protein (p.Arg79Gln). This variant is present in population databases (rs139576982, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of PNPLA2-related conditions (PMID: 32041611). ClinVar contains an entry for this variant (Variation ID: 465789). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects PNPLA2 function (PMID: 21170305). 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	RCV000528874	SCV001267682	likely benign	Neutral lipid storage myopathy	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000528874	SCV002767578	uncertain significance	Neutral lipid storage myopathy	2020-05-25	criteria provided, single submitter	clinical testing	A heterozygous missense variant was identified, NM_020376.3(PNPLA2):c.236G>A in exon 3 of 10 of the PNPLA2 gene. This substitution is predicted to create a minor amino acid change from arginine to glutamine at position 79 of the protein, NP_065109.1(PNPLA2):p.(Arg79Gln). The arginine at this position has high conservation (100 vertebrates, UCSC), and is located within the Patatin-like phospholipase domain. In silico software predicts this variant to be damaging (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a frequency of 0.07% (189 heterozygotes, 0 homozygotes). In addition, functional studies show that this variant causes impaired catalytic activity (Coassin, S. et al . (2010)). This variant has not been previously reported in clinical cases. Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS) with POTENTIAL CLINICAL RELEVANCE. Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Revvity Omics, Revvity	RCV000528874	SCV003813637	uncertain significance	Neutral lipid storage myopathy	2022-05-13	criteria provided, single submitter	clinical testing