Submissions for variant NM_002693.3(POLG):c.2218A>G (p.Asn740Asp)

gnomAD frequency: 0.00006  dbSNP: rs78347903

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000712792	SCV000242191	uncertain significance	not provided	2013-11-25	criteria provided, single submitter	clinical testing	p.Asn740Asp (AAC>GAC): c.2218 A>G in exon 13 of the POLG gene (NM_002693.2). The Asn740Asp missense change in the POLG gene has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. This variant is a non-conservative amino acid substitution of an uncharged Asparagine residue with a negatively charged Aspartic acid residue. While this variant alters a position that is not highly conserved across species and Asparagine is observed at this position in other species, several other missense mutations associated with POLG-related disorders are reported in this region of the protein (N736S, G737R, G746S, W748S). In silico analysis is inconsistent with regard to the effect this variant may have on the protein structure/function. Therefore, based on the currently available information, it is unclear whether Asn740Asp is a disease-causing mutation or a rare benign variant. The variant is found in INFANT-EPI panel(s).
Athena Diagnostics	RCV000712792	SCV000843321	uncertain significance	not provided	2018-01-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002317144	SCV000849828	uncertain significance	Inborn genetic diseases	2017-06-12	criteria provided, single submitter	clinical testing	The p.N740D variant (also known as c.2218A>G), located in coding exon 12 of the POLG gene, results from an A to G substitution at nucleotide position 2218. The asparagine at codon 740 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and aspartic acid is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Illumina Laboratory Services, Illumina	RCV001119420	SCV001277819	uncertain significance	POLG-Related Spectrum Disorders	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001372628	SCV001569304	uncertain significance	Progressive sclerosing poliodystrophy	2023-11-11	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 740 of the POLG protein (p.Asn740Asp). This variant is present in population databases (rs78347903, gnomAD 0.005%). This missense change has been observed in individual(s) with vascular dementia (PMID: 35307828). ClinVar contains an entry for this variant (Variation ID: 206519). 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 POLG protein function with a negative predictive value of 95%. 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.
New York Genome Center	RCV003448281	SCV004176114	uncertain significance	Progressive sclerosing poliodystrophy; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1; Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis; Mitochondrial DNA depletion syndrome 4b	2023-06-16	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000712792	SCV004236434	uncertain significance	not provided	2023-11-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000712792	SCV005075210	uncertain significance	not provided	2024-06-01	criteria provided, single submitter	clinical testing	POLG: PM2
Myllykangas group, University of Helsinki	RCV002051721	SCV001983991	uncertain significance	Vascular dementia	2021-10-01	no assertion criteria provided	research