Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000633669 | SCV000754930 | likely benign | Multiple gastrointestinal atresias | 2025-01-30 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002265829 | SCV002547535 | uncertain significance | not specified | 2022-05-12 | criteria provided, single submitter | clinical testing | Variant summary: TTC7A c.974G>A (p.Arg325Gln) results in a conservative amino acid change located in the Tetratricopeptide repeat protein 7, N-terminal domain (IPR045819) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00025 in 251184 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in TTC7A causing Severe Combined Immunodeficiency (0.00025 vs 0.00035), allowing no conclusion about variant significance. However, the frequency in the African subpopulation (0.0018) is much higher than estimated from disease prevalence. c.974G>A has been reported in the literature as a homozygous genotype in at-least two affected individuals with features of Primary Immunodeficiency who underwent a comprehensive NGS panel based diagnostic workup (example, Fusaro_2021, El-Daher_2019). At-least one of these two individuals reported a North African ethnicity (Fusaro_2021). One of these patients presented with recurrent lymphoproliferative syndrome and pan-hypergammaglobulinemia associated with chronic intestinal pseudo obstruction (CIPO) (El-Daher_2019). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (El-Daher_2019). The authors reported the mutant protein was unstable in B and T lymphoblasts leading to partial degradation, unable to stabilize subunits like EFR3 leading to low levels of EFR3 in B-cells and affected the ability of the mutant protein to regulate DNA accessibility, DNA stability and chromatin condensation. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
| Greenwood Genetic Center Diagnostic Laboratories, |
RCV002291285 | SCV002583709 | uncertain significance | not provided | 2022-09-21 | criteria provided, single submitter | clinical testing | PS3, PM3, BS1 |
| Fulgent Genetics, |
RCV002492961 | SCV002794227 | uncertain significance | Gastrointestinal defects and immunodeficiency syndrome 1 | 2022-01-28 | criteria provided, single submitter | clinical testing | |
| Illumina Laboratory Services, |
RCV002492961 | SCV004035987 | uncertain significance | Gastrointestinal defects and immunodeficiency syndrome 1 | 2023-05-15 | criteria provided, single submitter | clinical testing | The TTC7A c.974G>A (p.Arg325Gln) missense variant has been reported in a homozygous state in two individuals with features of gastrointestinal defects and immunodeficiency syndrome in the medical literature (PMID: 31787977; 32531373). The highest frequency of this allele in the Genome Aggregation Database is 0.001498 in the African/African American population (version 3.1.2). Functional studies conducted in patient cells demonstrate that this variant results in reduced protein expression and function (PMID: 31787977). The c.974G>A variant was detected in trans with a variant of uncertain significance in this proband. Based on the available evidence, the c.974G>A (p.Arg325Gln) variant is classified as a variant of uncertain significance for gastrointestinal defects and immunodeficiency syndrome. |