Submissions for variant NM_024753.5(TTC21B):c.3932G>A (p.Arg1311His)

gnomAD frequency: 0.00056  dbSNP: rs139327086

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000205446	SCV000259779	uncertain significance	Jeune thoracic dystrophy; Nephronophthisis	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1311 of the TTC21B protein (p.Arg1311His). This variant is present in population databases (rs139327086, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinically-diverse ciliopathies (PMID: 21258341). ClinVar contains an entry for this variant (Variation ID: 219735). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TTC21B protein function. 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.
Eurofins Ntd Llc (ga)	RCV000282631	SCV000336120	uncertain significance	not provided	2015-10-20	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001135464	SCV001295246	uncertain significance	Asphyxiating thoracic dystrophy 4	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001135465	SCV001295247	uncertain significance	Nephronophthisis 12	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV000282631	SCV002028949	uncertain significance	not provided	2021-11-18	criteria provided, single submitter	clinical testing	Reported in heterozygous state in a patient with renal and genital anomalies (Hilger et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26294094, 21258341)
Revvity Omics, Revvity	RCV000282631	SCV003821648	uncertain significance	not provided	2019-07-25	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000282631	SCV004147151	uncertain significance	not provided	2023-10-01	criteria provided, single submitter	clinical testing	TTC21B: PM2, BP4
Mayo Clinic Laboratories, Mayo Clinic	RCV000282631	SCV004224977	uncertain significance	not provided	2022-11-22	criteria provided, single submitter	clinical testing	BP4
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000282631	SCV004562754	uncertain significance	not provided	2023-10-18	criteria provided, single submitter	clinical testing	The TTC21B c.3932G>A; p.Arg1311His variant (rs139327086) is reported in the literature in an individual with renal and genital anomalies (Hilger 2015). This variant is also reported in ClinVar (Variation ID: 219735). It is observed in the general population with an overall allele frequency of 0.05% (151/282482 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.25). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Hilger AC et al. Targeted Resequencing of 29 Candidate Genes and Mouse Expression Studies Implicate ZIC3 and FOXF1 in Human VATER/VACTERL Association. Hum Mutat. 2015 Dec;36(12):1150-4. PMID: 26294094.