Submissions for variant NM_024753.5(TTC21B):c.1495G>A (p.Ala499Thr)

gnomAD frequency: 0.00001  dbSNP: rs866222900

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000498799	SCV000590301	uncertain significance	not provided	2017-06-26	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the TTC21B gene. The A499T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The A499T variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A499T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002524086	SCV003460728	uncertain significance	Jeune thoracic dystrophy; Nephronophthisis	2022-02-16	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 499 of the TTC21B protein (p.Ala499Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with short-rib thoracic dysplasia (PMID: 29068549). ClinVar contains an entry for this variant (Variation ID: 432560). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Dan Cohn Lab, University Of California Los Angeles	RCV000515896	SCV000612060	likely pathogenic	Jeune thoracic dystrophy	2017-06-01	no assertion criteria provided	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV000515896	SCV001479412	likely pathogenic	Jeune thoracic dystrophy		no assertion criteria provided	research