Submissions for variant NM_002693.3(POLG):c.328C>T (p.His110Tyr)

gnomAD frequency: 0.00026  dbSNP: rs139599587

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000727081	SCV000242309	uncertain significance	not provided	2022-08-05	criteria provided, single submitter	clinical testing	Reported previously in a female with hypotonia, failure to thrive, and short stature who did not have a second detectable variant in the POLG gene (Wong et al., 2008).; Reported previously in the heterozygous state in a child with chronic progressive external ophthalmoplegia and complex I deficiency with no second variant identified; however, segregation information was not provided (Sonam et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18546365, 20185557, 33469851, 32348839, 27826120, 28480171, 30214008, 26934580)
Invitae	RCV000461638	SCV000543880	uncertain significance	Progressive sclerosing poliodystrophy	2022-10-12	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 110 of the POLG protein (p.His110Tyr). This variant is present in population databases (rs139599587, gnomAD 0.08%). This missense change has been observed in individual(s) with clinical features of POLG-related conditions (PMID: 18546365, 27826120). ClinVar contains an entry for this variant (Variation ID: 206619). 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 expected to disrupt POLG protein function. Experimental studies have shown that this missense change does not substantially affect POLG function (PMID: 20185557). 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.
Eurofins Ntd Llc (ga)	RCV000727081	SCV000705481	uncertain significance	not provided	2017-01-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002317148	SCV000850916	uncertain significance	Inborn genetic diseases	2019-09-04	criteria provided, single submitter	clinical testing	The p.H110Y variant (also known as c.328C>T), located in coding exon 1 of the POLG gene, results from a C to T substitution at nucleotide position 328. The histidine at codon 110 is replaced by tyrosine, an amino acid with similar properties. This alteration has been reported in a three year old patient with some features of Alpers syndrome and in an eleven year old girl with CPEO plus syndrome (Wong LJ et al. Hum. Mutat., 2008 Sep;29:E150-72; Sonam K et al. Mitochondrion, 2017 Jan;32:42-49). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000461638	SCV000887181	benign	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.328C>T (NP_002684.1:p.His110Tyr) [GRCH38: NC_000015.10:g.89333427G>A] variant in POLG gene is interpretated to be a Benign based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. BS2:Observation of the variant in controls is inconsistent with penetrance of Mitochondrial DNA depletion syndrome 4A (Alpers type). BS3:Well-established functional studies show no deleterious effect. Based on the evidence criteria codes applied, the variant is suggested to be Benign.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000768048	SCV000898893	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	2021-03-30	criteria provided, single submitter	clinical testing	POLG NM_002693.2 exon 2 p.His110Tyr (c.328C>T): This variant has been reported in the literature in 1 individual with features of Alpers syndrome (hypotonia, failure to thrive, short stature and respiratory failure) (Wong 2008 PMID:18546365). This variant is present in 0.07% (19/24074) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/15-89876658-G-A). This variant is present in ClinVar (Variation ID:206619). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Functional studies involving yeast suggest that this variant may not impact the protein (Stumpf 2010 PMID:20185557). However, these studies may not accurately represent human biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Mayo Clinic Laboratories, Mayo Clinic	RCV000727081	SCV001716246	uncertain significance	not provided	2022-07-22	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000727081	SCV001879839	uncertain significance	not provided	2020-09-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001804925	SCV002051277	uncertain significance	not specified	2021-12-20	criteria provided, single submitter	clinical testing	Variant summary: POLG c.328C>T (p.His110Tyr) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 238934 control chromosomes (gnomAD). c.328C>T has been reported in the literature in individuals affected with features of Alpers syndrome, chronic progressive external ophthalmoplegia and sensory ataxic neuropathy with cerebellar syndrome (Wong_2008, Sonam_2017, Deepha_2021). These reports do not provide unequivocal conclusions about association of the variant with POLG-Related Spectrum Disorders. Experimental evidence evaluating an impact on protein function in yeast assays, demonstrated the variant to function similarly to wild-type (Stumpf_2010). Seven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and one ClinVar submitter (evaluation after 2014) cites it as benign. Based on the evidence outlined above, the variant was classified as uncertain significance.