Submissions for variant NM_020376.4(PNPLA2):c.326A>G (p.His109Arg)

gnomAD frequency: 0.00007  dbSNP: rs200683247

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000385511	SCV000374663	uncertain significance	Neutral lipid storage myopathy	2018-01-13	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000385511	SCV000641134	uncertain significance	Neutral lipid storage myopathy	2023-10-03	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 109 of the PNPLA2 protein (p.His109Arg). This variant is present in population databases (rs200683247, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with PNPLA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 306294). 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 not expected to disrupt PNPLA2 protein function. 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.
Baylor Genetics	RCV000385511	SCV001524604	uncertain significance	Neutral lipid storage myopathy	2019-08-08	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Revvity Omics, Revvity	RCV000385511	SCV003813639	uncertain significance	Neutral lipid storage myopathy	2019-12-02	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV004693068	SCV005191101	uncertain significance	not provided		criteria provided, single submitter	not provided
3billion, Medical Genetics	RCV000385511	SCV005328848	likely benign	Neutral lipid storage myopathy	2024-09-20	criteria provided, single submitter	clinical testing	The homozygous variant was found in patients diagnosed with another variant in a different gene, with no symptoms related to the gene containing the homozygous variant.