ClinVar Miner

Submissions for variant NM_018082.6(POLR3B):c.1244T>C (p.Met415Thr) (rs199504211)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000725610 SCV000338134 uncertain significance not provided 2018-05-30 criteria provided, single submitter clinical testing
GeneDx RCV000725610 SCV000517434 pathogenic not provided 2018-12-31 criteria provided, single submitter clinical testing The M415T variant in the POLR3B gene has been reported previously in a patient with cerebellar ataxia and hypogonadotropic hypogonadism who had a second POLR3B variant identified (Fogel et al., 2014). This variant has also been reported in two patients with hypogonadotropic hypogonadism who had a second POLR3B variant identified but no clinical features of neurological disease (Saffarini et al., 2015; Richards et al., 2017). Additionally, the M415T variant has been identified in multiple unrelated patients tested at GeneDx who had different pathogenic or likely pathogenic variants on the opposite allele (in trans). The M415T variant is observed in 150/126352 (0.1%) alleles from individuals of European background in large population cohorts and no individuals were reported to be homozygous (Lek et al., 2016). The M415T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, M415T is considered to be pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000765038 SCV000896235 uncertain significance Hypogonadotropic hypogonadism 7 with or without anosmia; Hypomyelinating leukodystrophy 7; Hypomyelinating leukodystrophy 8, with or without oligodontia and/or hypogonadotropic hypogonadism 2018-10-31 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV001262244 SCV001440040 likely pathogenic Hypomyelinating leukodystrophy 8, with or without oligodontia and/or hypogonadotropic hypogonadism 2019-01-01 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000725610 SCV001447782 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
GeneReviews RCV001262244 SCV001760683 pathogenic Hypomyelinating leukodystrophy 8, with or without oligodontia and/or hypogonadotropic hypogonadism 2017-05-11 no assertion criteria provided literature only

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