Submissions for variant NM_001558.4(IL10RA):c.170A>G (p.Tyr57Cys)

gnomAD frequency: 0.00009  dbSNP: rs201643277

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000282398	SCV000337829	likely pathogenic	not provided	2015-12-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000282398	SCV000617865	uncertain significance	not provided	2017-09-27	criteria provided, single submitter	clinical testing	The Y57C variant in the IL10RA gene has been reported previously in association with IL10RA-related disorder, in affected individuals who were compound heterozygous for the Y57C variant and another variant (Kotlarz et al., 2012; Engelhardt et al., 2013). The Y57C variant is observed in 24/126710 (0.02%) alleles from individuals of Finnish background, in the ExAC dataset (Lek et al., 2016). The Y57C 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. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret Y57C as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000804486	SCV000944397	likely pathogenic	Inflammatory bowel disease 28	2024-01-12	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 57 of the IL10RA protein (p.Tyr57Cys). This variant is present in population databases (rs201643277, gnomAD 0.02%). This missense change has been observed in individual(s) with early onset inflammatory bowel disease (PMID: 22549091, 23158016). 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: 284995). 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) performed at Invitae indicates that this missense variant is expected to disrupt IL10RA protein function with a positive predictive value of 80%. 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.
CeGaT Center for Human Genetics Tuebingen	RCV000282398	SCV001246867	likely pathogenic	not provided	2019-08-01	criteria provided, single submitter	clinical testing