ClinVar Miner

Submissions for variant NM_024753.5(TTC21B):c.626C>T (p.Pro209Leu) (rs140511594)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Broad Institute Rare Disease Group, Broad Institute 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 2017-12-20 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 209 of the TTC21B protein (p.Pro209Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs140511594, ExAC 0.03%). This variant has been reported to segregate with focal segmental glomerulosclerosis and nephronophthisis in many families (PMID: 21258341, 24876116). ClinVar contains an entry for this variant (Variation ID: 30935). Experimental studies have shown that this missense change leads to protein mislocalization, cytoskeleton alterations, and primary ciliary defects (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 2018-10-31 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
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.

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