ClinVar Miner

Submissions for variant NM_203290.4(POLR1C):c.835C>T (p.Arg279Trp)

gnomAD frequency: 0.00008  dbSNP: rs141156009
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000382254 SCV000330026 pathogenic not provided 2016-12-27 criteria provided, single submitter clinical testing The R279W variant in the POLR1C gene has been reported previously in an individual with Treacher Collinssyndrome who was compound heterozygous for the R279W variant and a truncating variant (Dauwerse et al., 2011).The R279W variant was not observed with any significant frequency in approximately 6500 individuals of Europeanand African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benignvariant in these populations. The R279W variant is a non-conservative amino acid substitution, which occurs at aposition that is conserved across species. In silico analysis predicts this variant is probably damaging to the proteinstructure/function. The functional importance of the R279 residue is supported by the presence of a different missensevariant (R279Q) reported in two affected siblings with TCS who harbored another POLR1C variant (phase notconfirmed), as well as in an unrelated individual with TCS who was compound heterozygous for R279Q and anonsense variant in POLR1C (Dauwerse et al., 2011). Therefore, we interpret R279W as a pathogenic variant.
MyeliNeuroGene Lab, McGill University Health Center Research Institute RCV000788033 SCV000924607 pathogenic Hypomyelinating leukodystrophy 11 criteria provided, single submitter research
Fulgent Genetics, Fulgent Genetics RCV005031454 SCV005670925 likely pathogenic Treacher Collins syndrome 3; Hypomyelinating leukodystrophy 11 2024-02-27 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000382254 SCV005762097 pathogenic not provided 2024-12-09 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 279 of the POLR1C protein (p.Arg279Trp). This variant is present in population databases (rs141156009, gnomAD 0.02%). This missense change has been observed in individual(s) with Treacher Collins syndrome (PMID: 21131976). 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: 30815). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt POLR1C protein function with a positive predictive value of 80%. This variant disrupts the p.Arg279 amino acid residue in POLR1C. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21131976, 30957429). 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.
OMIM RCV000023800 SCV000045091 pathogenic Treacher Collins syndrome 3 2011-01-01 no assertion criteria provided literature only

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