Submissions for variant NM_032193.3(RNASEH2C):c.205C>T (p.Arg69Trp) (rs78635798)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000414153	SCV000344847	likely pathogenic	not provided	2016-08-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000414153	SCV000490775	pathogenic	not provided	2018-01-04	criteria provided, single submitter	clinical testing	The R69W pathogenic variant in the RNASEH2C gene has been reported previously in the homozygous state in multiple individuals from South Asia or the Middle East with Aicardi-Goutieres syndrome, including two siblings with significantly different presentations, suggesting clinical variability (Rice et al., 2007; Ramantani et al., 2010; Vogt et al., 2013; Al-Shamsi et al., 2016; Hebbar et al., 2018). The R69W variant is observed in 21/30,782 (0.068%) alleles from individuals of South Asian background in large population cohorts (Lek et al., 2016). The R69W 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. Functional studies demonstrate that R69W is associated with decreased enzyme activity and reduced thermal stability of RNaseH2 (Chon et al., 2009; Reijns et al., 2011). We interpret R69W as a pathogenic variant.
SIB Swiss Institute of Bioinformatics	RCV000001322	SCV000803569	likely pathogenic	Aicardi Goutieres syndrome 3	2018-05-31	criteria provided, single submitter	curation	This variant is interpreted as a Likely Pathogenic, for Aicardi-Goutieres syndrome 3, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:23322642) (PMID:16845400). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Recurrent mutation observed in multiple patients. (PMID:17846997,16845400,20131292,23322642,29150899).
Fulgent Genetics,Fulgent Genetics	RCV000001322	SCV000893907	pathogenic	Aicardi Goutieres syndrome 3	2018-10-31	criteria provided, single submitter	clinical testing
Kariminejad - Najmabadi Pathology & Genetics Center	RCV000856709	SCV000999246	likely pathogenic	Neurodevelopmental delay	2018-08-13	criteria provided, single submitter	clinical testing
OMIM	RCV000001322	SCV000021472	pathogenic	Aicardi Goutieres syndrome 3	2013-02-01	no assertion criteria provided	literature only