Submissions for variant NM_002693.3(POLG):c.3650C>T (p.Ala1217Val)

gnomAD frequency: 0.00006  dbSNP: rs199751339

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766619	SCV000242255	uncertain significance	not provided	2019-08-09	criteria provided, single submitter	clinical testing	Reported previously in an individual with sensory ataxic neuropathy dysarthria and ophthalmoparesis (SANDO) who had a second POLG variant identified as well as a variant in the SLC25A4 gene and a mtDNA deletion in muscle (Tanaka et al., 2013).; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23524600, 27987238)
Athena Diagnostics Inc	RCV000188632	SCV000614730	uncertain significance	not specified	2017-03-28	criteria provided, single submitter	clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000758560	SCV000887303	uncertain significance	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.3650C>T (NP_002684.1:p.Ala1217Val) [GRCH38: NC_000015.10:g.89316821G>A] variant in FANCI gene is interpretated to be a Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. PP3:Computational evidence/predictors indicate the variant has deleterious effect on FANCI structure, function, or protein-protein interaction. Based on the evidence criteria codes applied, the variant is suggested to be Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV000765233	SCV000896469	uncertain significance	Progressive sclerosing poliodystrophy; Mitochondrial DNA depletion syndrome 1; 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	2021-11-24	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001116313	SCV001274369	uncertain significance	Fanconi anemia complementation group I	2017-11-17	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.
Illumina Laboratory Services, Illumina	RCV001116314	SCV001274370	uncertain significance	POLG-Related Spectrum Disorders	2017-11-15	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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Invitae	RCV000758560	SCV001518280	uncertain significance	Progressive sclerosing poliodystrophy	2022-08-15	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1217 of the POLG protein (p.Ala1217Val). This variant is present in population databases (rs199751339, gnomAD 0.08%). This missense change has been observed in individual(s) with sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO) (PMID: 23524600). ClinVar contains an entry for this variant (Variation ID: 206575). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on POLG function (PMID: 27987238). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000766619	SCV001961529	uncertain significance	not provided	2021-08-01	criteria provided, single submitter	clinical testing