Submissions for variant NM_024753.5(TTC21B):c.626C>T (p.Pro209Leu)

gnomAD frequency: 0.00011  dbSNP: rs140511594

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000023924	SCV000693904	pathogenic	Nephronophthisis 12	2017-06-26	criteria provided, single submitter	research	Previously reported homozygous missense mutation (p.P209L) in the TTC21B gene in seven families with FSGS (PMID: 26940125).
Gharavi Laboratory, Columbia University	RCV000681870	SCV000809349	pathogenic	not provided	2018-09-16	criteria provided, single submitter	research
Invitae	RCV000685092	SCV000812564	pathogenic	Jeune thoracic dystrophy; Nephronophthisis	2024-01-14	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 209 of the TTC21B protein (p.Pro209Leu). This variant is present in population databases (rs140511594, gnomAD 0.08%). This missense change has been observed in individual(s) with focal segmental glomerulosclerosis and nephronophthisis (PMID: 21258341, 24876116). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30935). 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. Experimental studies have shown that this missense change affects TTC21B function (PMID: 21258341, 24876116). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763456	SCV000894233	pathogenic	Asphyxiating thoracic dystrophy 4; Nephronophthisis 12	2022-05-19	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000023924	SCV000965772	pathogenic	Nephronophthisis 12	2015-01-01	criteria provided, single submitter	clinical testing
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000857219	SCV000999803	pathogenic	Infantile nephronophthisis	2019-01-28	criteria provided, single submitter	clinical testing	This variant was identified in composite heterozygosity with another variant in the same gene in a female patient with nephronophtisis, retinopathy and suspected ciliopathy
Blueprint Genetics	RCV001074967	SCV001240574	pathogenic	Retinal dystrophy	2017-09-22	criteria provided, single submitter	clinical testing
Molecular Biology Laboratory, Fundació Puigvert	RCV000023924	SCV001425282	likely pathogenic	Nephronophthisis 12	2020-02-01	criteria provided, single submitter	research
GeneDx	RCV000681870	SCV001805755	pathogenic	not provided	2022-04-25	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect (Huynh Cong et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24876116, 21258341, 29127259, 31456290, 32714622, 33599192, 34426522, 33712733, 31589614, 33226606, 33547761, 33532864, 26940125)
Revvity Omics, Revvity	RCV000681870	SCV002022453	pathogenic	not provided	2019-11-24	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002251925	SCV002523162	pathogenic	See cases	2021-05-10	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3, PM3, PP1, PP3
Eurofins-Biomnis	RCV000023924	SCV003935133	pathogenic	Nephronophthisis 12	2022-12-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004528134	SCV004107728	pathogenic	TTC21B-related disorder	2023-07-31	criteria provided, single submitter	clinical testing	The TTC21B c.626C>T variant is predicted to result in the amino acid substitution p.Pro209Leu. This variant was reported in the homozygous or compound heterozygous state in multiple individuals with nephronophthisis or focal segmental glomerulosclerosis (FSGS) (Davis et al. 2011. PubMed ID: 21258341; Bullich et al. 2017. PubMed ID: 26940125; Cong et al. 2014. PubMed ID: 24876116). This variant is reported in 0.077% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-166797621-G-A) and has been interpreted in ClinVar as pathogenic/likely pathogenic by multiple submitters (https://preview.ncbi.nlm.nih.gov/clinvar/variation/30935/). This variant is interpreted as pathogenic.
OMIM	RCV000023924	SCV000045215	pathogenic	Nephronophthisis 12	2011-03-01	no assertion criteria provided	literature only
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000786982	SCV000925888	pathogenic	Finnish congenital nephrotic syndrome	2018-11-21	no assertion criteria provided	clinical testing
Sharon lab, Hadassah-Hebrew University Medical Center	RCV001003236	SCV001161315	likely pathogenic	Renal dysplasia and retinal aplasia	2019-06-23	no assertion criteria provided	research
Sydney Genome Diagnostics, Children's Hospital Westmead	RCV001328175	SCV001449463	pathogenic	Nephrotic syndrome	2018-05-03	no assertion criteria provided	clinical testing	This patient is homozygous for a known pathogenic variant, c.626C>T p.(Pro209Leu), in the TTC21B gene. This variant (dbSNP: rs140511594), in the homozygous state, has been previously reported in patients with nephronophthisis and focal segmental glomerulosclerosis (FSGS) (Davis et al 2011 Nat Genet 43:189-196; Cong et al 2014 J Am Soc Nephrol 25:2435-2443; Bullich et al 2017 Nephrol Dial Transplant 32:151-156). Bullich et al 2017 also reported hypertension in some patients homozygous for p.(Pro209Leu). This variant was found in patients of North Africian or Portuguese descent. Functional studies showed the p.Pro209Leu variant partially altered cilia structure, cell migration and cytoskeleton suggesting a hypomorphic allele (Davis et al 2011; Cong et al 2014; Bullich et al 2017). This variant is considered to be pathogenic according to the ACMG guidelines.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000681870	SCV001807047	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000681870	SCV001929844	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000681870	SCV001952961	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Yale Center for Mendelian Genomics, Yale University	RCV001328175	SCV002107060	likely pathogenic	Nephrotic syndrome	2017-11-10	no assertion criteria provided	literature only
Genomics And Bioinformatics Analysis Resource, Columbia University	RCV000023924	SCV004024139	pathogenic	Nephronophthisis 12		no assertion criteria provided	research