Submissions for variant NM_020458.4(TTC7A):c.1630del (p.Leu544fs)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282917	SCV002570921	likely pathogenic	Gastrointestinal defect and immunodeficiency syndrome	2022-07-15	criteria provided, single submitter	clinical testing	Variant summary: TTC7A c.1630delC (p.Leu544SerfsX16) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic within ClinVar (e.g. c.1673_1674insG [p.Leu559fs], c.1869C>A [p.Cys623Ter]). The variant allele was found at a frequency of 1.2e-05 in 241294 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1630delC in individuals affected with Gastrointestinal Defects And Immunodeficiency Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003096347	SCV003230955	pathogenic	Multiple gastrointestinal atresias	2022-09-13	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with TTC7A-related conditions. For these reasons, this variant has been classified as Pathogenic. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Leu544Serfs*16) in the TTC7A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TTC7A are known to be pathogenic (PMID: 23830146, 24292712).