ClinVar Genomic variation as it relates to human health

Converted during submission to Uncertain significance.

Variant summary: TTC7A c.1817A>G (p.Lys606Arg) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0021 in 251304 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 6-fold the estimated maximal expected allele frequency for a pathogenic variant in TTC7A causing Severe Combined Immunodeficiency Syndrome phenotype (0.00035), suggesting that the variant is benign. c.1817A>G has been reported in the literature in cis with c.2014T>C, p.Ser672Pro in at least one individual affected with Combined Immunodeficiency with Multiple Intestinal Atresias (CID-MIA), who had a likely pathogenic variant (c.1000DelAAGT) in compound heterozygosity (e.g. Chen_2013). The variant has also been detected in several patients with early-onset inflammatory bowel disease (EOIBD) or inflammatory bowel disease (IBD), often occurring along with c.2014T>C, p.Ser672Pro (e.g. Kammermeier_2016, Petersen_2017, Ashton, 2020). In some cases, the variants were indicated to have been inherited as a complex allele, while in others, the phase was not reported. However, these two variants were also reported in trans in at least one individual affected by a mild form of Combined Variable Immunodeficiency Syndrome (CVID), suggesting that the variants could possibly be associated with a mild form of disease when found on separate alleles (e.g. Lawless_2017). The c.1817A>G and c.2014T>C variants were also reported in compound heterozygosity in an individual evaluated for IPEX (Immune Dysregulation, Polyendocrinopathy, Ebteropathy, X-Linked) Syndrome (e.g. Gambineri_2018). These findings do not provide unequivocal evidence for association of the variant with Severe Combined Immunodeficiency Syndrome. To the best of our knowledge, no experimental studies evaluating an impact on protein function have been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory cited the variant as likely benign, and one laboratory cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

PM3_Supporting, BS1

Has been observed in with the S672P variant in multiple cases; in cases where phase was determined, it has been observed in cis with S672P in one individual with combined immunodeficiency with multiple intestinal atresias who harbored an another TTC7A variant in trans (Chen et al., 2013), and has also been observed in trans with the S672P in another individual with common variable immunodeficiency (Lawless et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In addition, in silico splice predictors suggest this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 28930861, 30443250, 23830146, 28808844, 27418642, 31814065)

Criteria applied: PS4_MOD, PS3_SUP, PP3

TTC7A: BS1

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).