Submissions for variant NM_002693.3(POLG):c.2870C>T (p.Ala957Val)

gnomAD frequency: 0.00001  dbSNP: rs753160398

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000304218	SCV000329727	pathogenic	not provided	2020-09-28	criteria provided, single submitter	clinical testing	Multiple pathogenic missense variants at this residue (p.A957S and p.A957P) have been reported in association with POLG-related disorders (Stenson et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 25466440, 21880868, 32234506, 32703289)
Eurofins Ntd Llc (ga)	RCV000304218	SCV000339866	likely pathogenic	not provided	2016-04-04	criteria provided, single submitter	clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000758268	SCV000886916	pathogenic	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.2870C>T (NP_002684.1:p.Ala957Val) [GRCH38: NC_000015.10:g.89320877G>A] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:21880868 . This variant meets the following evidence codes reported in the ACMG-guideline. PS1:This variation causes same amino-acid change as an established pathogenic variant. PS3:Well established functional studies show a deleterious effect on POLG. PM2:This variant is absent in key population databases. PM3:Detected in trans with a pathogenic variant for Mitochondrial DNA depletion syndrome 4A (Alpers type) which is a recessive disorder. PP1:This variant is co-segregated with Mitochondrial DNA depletion syndrome 4A (Alpers type) in multiple affected family members. PP4:Patient's phenotype or family history is highly specific for POLG. Based on the evidence criteria codes applied, the variant is suggested to be Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000758268	SCV001374132	pathogenic	Progressive sclerosing poliodystrophy	2023-07-27	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 957 of the POLG protein (p.Ala957Val). This variant is present in population databases (rs753160398, gnomAD 0.003%). This missense change has been observed in individuals with clinical features of autosomal recessive POLG-related conditions (PMID: 21880868, 25466440, 32703289). ClinVar contains an entry for this variant (Variation ID: 280016). 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. This variant disrupts the p.Ala957 amino acid residue in POLG. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12210792, 15258572, 15689359, 23208208, 29915382). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV000304218	SCV002502898	likely pathogenic	not provided	2022-02-28	criteria provided, single submitter	clinical testing