2-165941111-G-A
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_024753.5(TTC21B):c.626C>T(p.Pro209Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000799 in 1,613,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_024753.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TTC21B | NM_024753.5 | c.626C>T | p.Pro209Leu | missense_variant | Exon 6 of 29 | ENST00000243344.8 | NP_079029.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000112 AC: 17AN: 152104Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000127 AC: 32AN: 251118Hom.: 0 AF XY: 0.000140 AC XY: 19AN XY: 135698
GnomAD4 exome AF: 0.0000766 AC: 112AN: 1461614Hom.: 0 Cov.: 32 AF XY: 0.0000756 AC XY: 55AN XY: 727108
GnomAD4 genome AF: 0.000112 AC: 17AN: 152222Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10AN XY: 74428
ClinVar
Submissions by phenotype
Nephronophthisis 12 Pathogenic:6
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Previously reported homozygous missense mutation (p.P209L) in the TTC21B gene in seven families with FSGS (PMID: 26940125). -
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not provided Pathogenic:6
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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) -
Nephrotic syndrome Pathogenic:2
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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. -
Asphyxiating thoracic dystrophy 4;C3151186:Nephronophthisis 12 Pathogenic:1
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Jeune thoracic dystrophy;C0687120:Nephronophthisis Pathogenic:1
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). Invitae Evidence 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 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. -
See cases Pathogenic:1
ACMG classification criteria: PS3, PM3, PP1, PP3 -
TTC21B-related disorder Pathogenic:1
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 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. -
Finnish congenital nephrotic syndrome Pathogenic:1
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Renal dysplasia and retinal aplasia Pathogenic:1
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Retinal dystrophy Pathogenic:1
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Infantile nephronophthisis Pathogenic:1
This variant was identified in composite heterozygosity with another variant in the same gene in a female patient with nephronophtisis, retinopathy and suspected ciliopathy -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at