Submissions for variant NM_020458.4(TTC7A):c.1817A>G (p.Lys606Arg)

gnomAD frequency: 0.00216  dbSNP: rs139010200

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000427110	SCV000511632	uncertain significance	not provided	2016-10-25	criteria provided, single submitter	clinical testing	Converted during submission to Uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081099	SCV000630304	likely benign	Multiple gastrointestinal atresias	2025-02-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001280647	SCV001467888	uncertain significance	not specified	2020-12-13	criteria provided, single submitter	clinical testing	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.
CeGaT Center for Human Genetics Tuebingen	RCV000427110	SCV001502294	likely benign	not provided	2022-09-01	criteria provided, single submitter	clinical testing	TTC7A: BS1
GeneDx	RCV000427110	SCV001817751	uncertain significance	not provided	2021-11-09	criteria provided, single submitter	clinical testing	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)
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000427110	SCV002583707	uncertain significance	not provided	2022-09-21	criteria provided, single submitter	clinical testing	PM3_Supporting, BS1
Institute of Human Genetics, University of Leipzig Medical Center	RCV003227731	SCV003925639	uncertain significance	Gastrointestinal defects and immunodeficiency syndrome 1	2023-04-11	criteria provided, single submitter	clinical testing	Criteria applied: PS4_MOD, PS3_SUP, PP3
PreventionGenetics, part of Exact Sciences	RCV003919994	SCV004729857	likely benign	TTC7A-related disorder	2019-09-04	no assertion criteria provided	clinical testing	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).