Submissions for variant NM_002693.3(POLG):c.1837C>T (p.His613Tyr)

gnomAD frequency: 0.00166  dbSNP: rs147407423

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000173762	SCV000224911	benign	not specified	2015-04-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000710183	SCV000242291	uncertain significance	not provided	2024-09-05	criteria provided, single submitter	clinical testing	Reported as a variant of uncertain clinical significance in two unrelated individuals with clinical features suggestive of POLG deficiency who were heterozygous for p.(H613Y) and did not have another identifiable POLG variant (PMID: 21880868, 28130605). One individual inherited the p.(H613Y) variant from an apparently unaffected father (PMID: 28130605); 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: 32019516, 28130605, 28480171, 26934580, 25356899, 28569743, 30814510, 25032700, 21880868, 37256495)
Genetic Services Laboratory, University of Chicago	RCV000173762	SCV000596502	uncertain significance	not specified	2015-12-14	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000173762	SCV000604902	uncertain significance	not specified	2017-01-17	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000710183	SCV000614708	likely benign	not provided	2023-04-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000538134	SCV000630113	likely benign	Progressive sclerosing poliodystrophy	2024-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002313026	SCV000848674	uncertain significance	Inborn genetic diseases	2018-04-26	criteria provided, single submitter	clinical testing	The p.H613Y variant (also known as c.1837C>T), located in coding exon 9 of the POLG gene, results from a C to T substitution at nucleotide position 1837. The histidine at codon 613 is replaced by tyrosine, an amino acid with similar properties. This alteration was found in the heterozygous state in an individual with ptosis, myopathy, severe cerebellar atrophy, dysarthria, and mild cognitive impairment; and it was inherited from his healthy father (Da Pozzo P et al. Neurol. Sci., 2017 Apr;38:563-570). 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	RCV000538134	SCV000887100	benign	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.1837C>T (NP_002684.1:p.His613Tyr) [GRCH38: NC_000015.10:g.89325562G>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. BS1:The minor allele frequency of this allele is high for Mitochondrial DNA depletion syndrome 4A (Alpers type). BS2:Observation of the variant in controls is inconsistent with penetrance of Mitochondrial DNA depletion syndrome 4A (Alpers type). 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	RCV000768055	SCV000898900	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 10 p.His613Tyr (c.1837C>T): This variant has been reported in the literature in at least two individuals with clinical features of POLG related disease (Tang 2011 PMID:21880868, Da Pozzo 2017 PMID:28130605) and has been identified by our laboratory in at least two individuals with epilepsy. This variant is present in 0.5% (134/24022) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/15-89868793-G-A), and it is present in ClinVar (Variation ID:193643). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. However, the variant Tyrosine (Tyr) amino acid is present in 2 other species (Chinese Softshell Turtle, Spiny Softshell Turtle), suggesting that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
New York Genome Center	RCV001263354	SCV001441396	uncertain significance	Global developmental delay	2020-02-06	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000710183	SCV001715133	uncertain significance	not provided	2023-04-17	criteria provided, single submitter	clinical testing	BS1, PP3
Revvity Omics, Revvity	RCV000710183	SCV003809216	uncertain significance	not provided	2022-12-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000173762	SCV004813937	uncertain significance	not specified	2024-02-19	criteria provided, single submitter	clinical testing	Variant summary: POLG c.1837C>T (p.His613Tyr) 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 0.00029 in 1613624 control chromosomes, predominantly at a frequency of 0.0046 within the African or African-American subpopulation in the gnomAD database, including 1 homozygotes. c.1837C>T has been reported in the literature in an individual with features POLG-Related Spectrum Disorders (Pozzo_2017). This report does not provide unequivocal conclusions about association of the variant with POLG-Related Spectrum Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 28130605). ClinVar contains an entry for this variant (Variation ID: 193643). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003985737	SCV004750869	likely benign	POLG-related disorder	2019-06-23	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).