Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000794275 | SCV000933671 | likely pathogenic | Aicardi-Goutieres syndrome 2 | 2024-01-18 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 60 of the RNASEH2B protein (p.Leu60Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Aicardi-Goutieres syndrome (PMID: 16845400). 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: 641111). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RNASEH2B protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004689883 | SCV005185087 | likely pathogenic | Aicardi Goutieres syndrome | 2024-05-31 | criteria provided, single submitter | clinical testing | Variant summary: RNASEH2B c.179T>G (p.Leu60Arg) results in a non-conservative amino acid change located in the Rnh202, triple barrel domain (IPR041195) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251290 control chromosomes. c.179T>G has been reported in the literature in the compound heterozygous state in multiple individuals affected with Aicardi Goutieres Syndrome (example, Crow_2006, Rice_2017, McCreary_2019). These data indicate that the variant is likely to be associated with disease. One publication reports that this variant could not be expressed or purified in an E. coli background, however this information does not allow convincing conclusions about the variant effect (Figiel_2011). The following publications have been ascertained in the context of this evaluation (PMID: 25604658, 16845400, 21177858, 31664448, 17846997, 27943079). ClinVar contains an entry for this variant (Variation ID: 641111). Based on the evidence outlined above, the variant was classified as likely pathogenic. |