Submissions for variant NM_002693.3(POLG):c.3405C>T (p.Asp1135=)

gnomAD frequency: 0.00006  dbSNP: rs2307445

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	RCV001526404	SCV001736742	uncertain significance	Mitochondrial disease	2021-05-06	reviewed by expert panel	curation	The c.3405C>T (p.Asp1135=) variant in POLG is present in population databases at the following frequencies: ESP Allele Frequency: 0.00023 with 0 homozygotes (PM2). This is a silent variant and no change in amino acid (BP7). In summary, there is insufficient evidence to characterize this variant and therefore it remains a variant of uncertain significance for primary mitochondrial disease inherited in an autosomal recessive manner. ntDNA Mitochondrial ACMG-AMP Criteria for POLG applied: PM2, BP7
GeneDx	RCV000431112	SCV000534011	likely benign	not specified	2016-11-23	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000633563	SCV000754809	likely benign	Progressive sclerosing poliodystrophy	2023-11-13	criteria provided, single submitter	clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000633563	SCV000887279	benign	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.3405C>T (NP_002684.1:p.Asp1135=) [GRCH38: NC_000015.10:g.89318618G>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). BP7:The variant is silent with non predicted splice impact. Based on the evidence criteria codes applied, the variant is suggested to be Benign.
CeGaT Center for Human Genetics Tuebingen	RCV003401433	SCV004137621	likely benign	not provided	2022-05-01	criteria provided, single submitter	clinical testing	POLG: BP4, BP7