TECR

Inheritance Pattern: AR

Disease ID:MONDO:0001071

Submitter: ClinGen

The *TECR* gene, located on chromosome 19 at 19p13.12, encodes a synaptic glycoprotein that catalyzes the final reduction step in the elongation of very long chain fatty acids. *TECR* was first reported in relation to non-syndromic autosomal recessive intellectual disability in 2011 (Caliskan et al., PMID: 21212097). The authors described a large consanguineous Hutterite family in which 5 of 15 siblings were affected by mild to moderate intellectual disability, dysmorphic features and intention tremors. All 5 affected siblings were found to be homozygous for a missense mutation in exon 8 of the *TECR* gene, which results in the substitution of a leucine for a highly conserved proline at amino acid 182, whereas the 9 unaffected siblings and their parents were all heterozygous for this variant. In total, 1523 individuals in the same religious community were genotyped, and despite a high carrier frequency of this mutation (1 in 14) none of the other carriers were married to each other. Nineteen unique variants have been reported (1 pathogenic, 6 variants of uncertain significance, 9 likely benign, 3 benign). The mechanism by which the *TECR* P182L mutation causes intellectual disability is not fully understood, but in 2013, Abe et al. (PMID: 24220030) demonstrated that yeast transfected with the P182L mutation show an approximately 80% reduction in TECR enzyme stability and activity relative to their wild-type counterparts. Abe et al. propose that in contrast to *TECR* null mutations, which are lethal, this mutation may be mild enough to alter sphingolipid activity in the nervous system while sparing other body systems. In 2021, Uchida et al. (PMID: 33482198) demonstrated that TECR binds to SERCA2b, an ATPase involved in transporting Ca2+ from the cytosol into the endoplasmic reticulum lumen. This work suggests that in addition to its importance in the elongation of very long chain fatty acids, TECR is also an important regulator of Ca2+ signaling, which is mechanistically important for synaptic potentiation, learning and memory. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts this gene-disease relationship. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on March 10, 2022 (SOP Version 8).

Inheritance Pattern: AR

Disease ID:MONDO:0013528

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0013528

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0013528

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0019502

Submitter: Orphanet