Submissions for variant NM_020458.4(TTC7A):c.1288-1G>T

dbSNP: rs568082272

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001215172	SCV001386902	pathogenic	Multiple gastrointestinal atresias	2019-07-18	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 10 of the TTC7A gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with clinical features of gastrointestinal defects and immunodeficiency syndrome. In that individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant (Invitae). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TTC7A are known to be pathogenic (PMID: 23830146, 24292712). For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002272412	SCV002557038	likely pathogenic	Gastrointestinal defects and immunodeficiency syndrome 1	2020-05-21	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 Loss-of-function is a known mechanism of disease for this gene. (N) 0106 This gene is known to be associated with autosomal recessive disease. (N) 0211 Canonical splice site variant without proven consequence on splicing (no functional evidence available). (P) 0251 Variant is heterozygous. (N) 0301 Variant is absent from gnomAD. (P) 0309 An alternative amino acid change at the same position has been observed in gnomAD (1 heterozygote, 0 homozygotes). (N) 0505 Abnormal splicing is predicted by in-silico tools and affected nucleotide is highly conserved. (P) 0705 No comparable variants have previous evidence for pathogenicity. (N) 0807 Variant has not previously been reported in a clinical context. (N) 0905 No segregation evidence has been identified for this variant. (N) 1007 No published functional evidence has been identified for this variant. (N) 1201 Heterozygous variant detected in trans with a second pathogenic heterozygous variant in a recessive disease. (P) 1206 Variant is paternally inherited. (N)