rs121918044

  • Pathogenic/Likely pathogenic

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Description

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

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: 24288107, 20601675, 16639411, 21880868, 16368709, 22006280, 11431686, 30634555, 31521625, 32161153, 31589614, 33469851)

The NM_002693.2:c.911T>G (NP_002684.1:p.Leu304Arg) [GRCH38: NC_000015.10:g.89329055A>C] variant in POLG gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:11431686 . This variant meets the following evidence codes reported in the ACMG-guideline. 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. PP2:This is a missense variant in POLG with a low rate of benign and high rate of pathogenic missense variations. PP3:Computational evidence/predictors indicate the variant has deleterious effect on POLG structure, function, or protein-protein interaction. 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 Likely Pathogenic.

This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 304 of the POLG protein (p.Leu304Arg). This variant is present in population databases (rs121918044, gnomAD 0.04%). This missense change has been observed in individual(s) with autosomal recessive POLG-related disorders (PMID: 11431686, 16639411, 21880868, 22006280, 24288107). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 13497). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects POLG function (PMID: 20601675, 26095671). For these reasons, this variant has been classified as Pathogenic.

Reference Allele

A


Alternative Allele

C

Chromosome

15


Location

89329055


Variant Type

SNP

Genes

ClinVar

Name

NM_002693.3(POLG):c.911T>G (p.Leu304Arg)


Allele

C


Clinical Significance

Pathogenic/Likely pathogenic

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