ClinVar Miner

Submissions for variant NM_203290.4(POLR1C):c.193A>G (p.Met65Val)

gnomAD frequency: 0.00100  dbSNP: rs141471029
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services,Illumina RCV000390190 SCV000463446 uncertain significance POLR1C-Related Disorders 2016-06-14 criteria provided, single submitter clinical testing The c.193A>G (p.Met65Val) variant has been reported in one study in which it is found in a compound heterozygous state with another missense variant in an individual with a clinical phenotype of leukodystrophy, hypomyelinating (Thiffault et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.00174 in the European American population of the Exome Sequencing Project. The evidence for this variant is limited. The p.Met65Val variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for POLR1C-related disorders.
Illumina Laboratory Services,Illumina RCV000778794 SCV000915165 uncertain significance Hypomyelinating leukodystrophy 11 2017-09-05 criteria provided, single submitter clinical testing The POLR1C c.193A>G (p.Met65Val) missense variant has been reported in one study in which it is found in a compound heterozygous state with another missense variant in an individual with hypomyelinating leukodystrophy (Thiffault et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.00174 in the European American population of the Exome Sequencing Project. The evidence for this variant is limited. The p.Met65Val variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for Pol III-related leukodystrophy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
MyeliNeuroGene Lab, McGill University Health Center Research Institute RCV000778794 SCV000924590 pathogenic Hypomyelinating leukodystrophy 11 criteria provided, single submitter research
Institute of Human Genetics, University of Leipzig Medical Center RCV000778794 SCV001440015 uncertain significance Hypomyelinating leukodystrophy 11 2019-01-01 criteria provided, single submitter clinical testing
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center RCV001375152 SCV001572110 uncertain significance Hearing impairment 2021-04-12 criteria provided, single submitter clinical testing PS1_Strong, PP3_Supporting, BS1_Supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000390190 SCV002051432 likely pathogenic POLR1C-Related Disorders 2021-12-30 criteria provided, single submitter clinical testing Variant summary: POLR1C c.193A>G (p.Met65Val) results in a conservative amino acid change located in the DNA-directed RNA polymerase, RpoA/D/Rpb3-type domain (IPR011263) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00085 in 251490 control chromosomes, predominantly at a frequency of 0.0015 within the Non-Finnish European subpopulation in the gnomAD database. c.193A>G has been reported in the literature in three compound heterozygous individuals affected with Hypomyelinating Leukodystrophy (Thiffault_2015, Gauquelin_2019, Ching-Lopez_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have assessed the variant since 2014: four have classified the variant as uncertain significance, and one as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Genetic Services Laboratory,University of Chicago RCV001814980 SCV002062020 uncertain significance not specified 2017-11-28 criteria provided, single submitter clinical testing
Invitae RCV001861282 SCV002196685 uncertain significance not provided 2021-12-03 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 65 of the POLR1C protein (p.Met65Val). This variant is present in population databases (rs141471029, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with leukodystrophy (PMID: 26151409, 33804237). ClinVar contains an entry for this variant (Variation ID: 356872). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Center for Human Genetics Tuebingen RCV001861282 SCV002586118 uncertain significance not provided 2022-08-01 criteria provided, single submitter clinical testing
GeneReviews RCV000778794 SCV001760708 not provided Hypomyelinating leukodystrophy 11 no assertion provided literature only

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