SARS2

Inheritance Pattern: AR

Disease ID:MONDO:0013458

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0013458

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0013458

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0013458

Submitter: Natera

Inheritance Pattern: AR

Disease ID:MONDO:0013458

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0013458

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *SARS2* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of June 6, 2022. The *SARS2* gene encodes mitochondrial seryl-tRNA synthetase 2, one of the mitochondrial aminoacyl-tRNA synthetases, which function in mitochondrial translation by catalyzing the attachment of amino acids to their cognate tRNAs. Defects in tRNA charging can result in impaired synthesis of oxidative phosphorylation complex protein subunits. The *SARS2* gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2011 (PMID: 21255763). While various names have been given to the constellation of features seen in those with *SARS2*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *SARS2* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included nine unique variants, including eight missense variants and one splice-site variant. Nine probands were reported in nine publications between 2011-2022 (PMIDs: 21255763, 24034276, 33751860, 34407605, 35445976, 33972171, 27279129, 28716262, 31607746). The condition was first described in a consanguineous family from Palestine in a male proband and a similarly affected female cousin with early onset severe hyperuricemia, pulmonary hypertension, progressive renal failure, alkalosis, anemia, and elevated blood lactate levels (referred to by the acronym HUPRA syndrome for **h**yper**u**ricemia, **p**ulmonary hypertension, **r**enal failure, and **a**lkalosis). Subsequent publications have reported five additional cases with a consistently severe phenotype characterized by progressive kidney failure and pulmonary hypertension. In addition, there have been three reports of individuals with a predominant spastic paresis phenotype with infantile or childhood onset associated with a variable developmental delay and/or intellectual disability. No segregation data were available. Loss or altered function is proposed as the mechanism of disease. This gene-disease relationship is also supported by its known biochemical function that is shared with other genes associated with primary mitochondrial disease. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on June 6, 2022 (SOP Version 8).