ClinVar Miner

Submissions for variant NM_032193.4(RNASEH2C):c.227C>T (p.Pro76Leu)

gnomAD frequency: 0.00001  dbSNP: rs76091978
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Center for Human Genetics Tuebingen RCV000994660 SCV001148330 likely pathogenic not provided 2017-10-01 criteria provided, single submitter clinical testing
Neuberg Centre For Genomic Medicine, NCGM RCV001823174 SCV002073275 likely pathogenic Aicardi-Goutieres syndrome 3 criteria provided, single submitter clinical testing The missense variant p.P76L in RNASEH2C (NM_032193.4) has been previously reported in homozygous form in affected individual (Rice G et al). It has been submitted to ClinVar as Likely Pathogenic. The p.P76L variant is observed in 1/18,382 (0.0054%) alleles from individuals of East Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes.In silico predictios are contradictory: SIFT- Tolerated, Polyphen-Damaging and the residue is conserved across species. For these reasons, this variant has been classified as Likely Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV001823174 SCV002258896 uncertain significance Aicardi-Goutieres syndrome 3 2022-10-13 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 76 of the RNASEH2C protein (p.Pro76Leu). This variant is present in population databases (rs76091978, gnomAD 0.006%). This missense change has been observed in individual(s) with Aicardi-Goutieres syndrome (PMID: 17846997). ClinVar contains an entry for this variant (Variation ID: 806694). 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. 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.
PreventionGenetics, part of Exact Sciences RCV004753159 SCV005354571 likely pathogenic RNASEH2C-related disorder 2024-05-27 no assertion criteria provided clinical testing The RNASEH2C c.227C>T variant is predicted to result in the amino acid substitution p.Pro76Leu. This variant was reported in the homozygous or compound heterozygous state in at least two individuals with Aicardi-Goutières syndrome (Rice et al 2007. PubMed ID: 17846997; https://pesquisa.bvsalud.org/portal/resource/pt/wpr-885580). This variant is located in a region of RNASE2C critical for heterotrimer formation and where several pathogenic variants are located (Reijns et al. 2011. PubMed ID: 21177854), and was functionally shown via laboratory methods to result in partial loss-of-function and subsequent increased migration of DNA from the nucleus (Günther et al. 2015. PubMed ID: 25500883). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as likely pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.