Submissions for variant NM_033629.6(TREX1):c.218C>T (p.Pro73Leu)

gnomAD frequency: 0.00001  dbSNP: rs755919767

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000626116	SCV000746743	uncertain significance	Aicardi-Goutieres syndrome 1	2017-12-18	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764509	SCV000895588	uncertain significance	Aicardi-Goutieres syndrome 1; Chilblain lupus 1; Systemic lupus erythematosus; Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations	2018-10-31	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000626116	SCV000992375	likely pathogenic	Aicardi-Goutieres syndrome 1	2019-06-18	criteria provided, single submitter	clinical testing	This TREX1 variant (rs755919767) is rare (<0.1%) in large population datasets (gnomAD: 6/250524 total alleles; 0.0024%; no homozygotes) and has not been reported in the literature, to our knowledge. There are conflicting interpretations of the pathogenicity of this variant in ClinVar. Two submitters classified it as a variant of uncertain clinical significance and one as pathogenic. Two bioinformatic tools queried predict that this substitution would be probably damaging/deleterious, and the proline residue at this position is evolutionarily conserved in mammals. This variant is considered to be likely pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000656254	SCV001153941	uncertain significance	not provided	2019-02-01	criteria provided, single submitter	clinical testing
Invitae	RCV001219467	SCV001391408	uncertain significance	Aicardi-Goutieres syndrome 1; Chilblain lupus 1; Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations	2024-01-14	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 73 of the TREX1 protein (p.Pro73Leu). This variant is present in population databases (rs755919767, gnomAD 0.01%). This missense change has been observed in individual(s) with increased CSF interferon alpha (PMID: 34440436). ClinVar contains an entry for this variant (Variation ID: 522920). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests 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.
GeneDx	RCV000656254	SCV001997054	uncertain significance	not provided	2021-04-09	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV000656254	SCV000778215	pathogenic	not provided	2016-09-26	no assertion criteria provided	clinical testing
Myelin Disorders Clinic-Children's Medical Center/Medical Genetics Lab-Tarbiat Modares University, Children's Medical Center, Pediatrics Center of Excellence,	RCV000626116	SCV001334141	uncertain significance	Aicardi-Goutieres syndrome 1		no assertion criteria provided	clinical testing