Submissions for variant NM_002693.3(POLG):c.3586G>A (p.Asp1196Asn)

gnomAD frequency: 0.00001  dbSNP: rs765344513

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188628	SCV000242251	uncertain significance	not provided	2024-08-26	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Reported in an individual with developmental delay, short stature, and myopathy (PMID: 18546365); This variant is associated with the following publications: (PMID: 18546365)
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000758333	SCV000886998	likely benign	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.3586G>A (NP_002684.1:p.Asp1196Asn) [GRCH38: NC_000015.10:g.89317433C>T] variant in POLG gene is interpretated to be a Likely Benign based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. BP4:Computational evidence/predictors indicate no impact on the POLG structure, function, or protein-protein interaction. BP6:Reputable source(s) without shared data suggest the variant is benign. Based on the evidence criteria codes applied, the variant is suggested to be Likely Benign.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847833	SCV002104877	uncertain significance	Hereditary spastic paraplegia	2020-11-25	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000758333	SCV002286752	uncertain significance	Progressive sclerosing poliodystrophy	2023-08-10	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1196 of the POLG protein (p.Asp1196Asn). 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. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on POLG protein function. ClinVar contains an entry for this variant (Variation ID: 206571). This missense change has been observed in individual(s) with clinical features of autosomal dominant POLG-related condition (PMID: 18546365). This variant is present in population databases (rs765344513, gnomAD 0.0009%).