ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.3550G>A (p.Asp1184Asn) (rs1131691575)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000493626 SCV000582409 pathogenic not provided 2018-10-31 criteria provided, single submitter clinical testing The D1184N variant in the POLG gene has been reported previously in multiple unrelated individuals with POLG-related disorders who had a second POLG variant identified (de Vries et al., 2007; Amiot et al., 2009; Blok et al., 2009). Functional studies show that D1184N results in mtDNA depletion as well as increased petite colony formation, suggesting it may be a null variant (Stumpf et al., 2010). The D1184N variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The D1184N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and a different missense variant in the same residue (D1184H) as well as missense variants in nearby residues (I1185T, I1185N, D1186H, C1188R) have been reported in the Human Gene Mutation Database in association with POLG-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, D1184N is considered a pathogenic variant.
Invitae RCV000814983 SCV000955423 pathogenic Progressive sclerosing poliodystrophy 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 1184 of the POLG protein (p.Asp1184Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with POLG-related disorders (PMID:16401742, 19578034) and is also known to segregate with POLG-related disorder in a family (PMID:16957900). ClinVar contains an entry for this variant (Variation ID: 426100). This variant has been reported to affect POLG protein function (PMID:20185557). For these reasons, this variant has been classified as Pathogenic.
Wellcome Centre for Mitochondrial Research,Newcastle University RCV000508838 SCV000575913 pathogenic Mitochondrial diseases 2017-04-07 no assertion criteria provided clinical testing

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