NM_024753.5(TTC21B):c.626C>T (p.Pro209Leu) AND Nephronophthisis 12

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: Dec 1, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000023924.10

Allele description

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

Genes:

TTC21B-AS1:TTC21B antisense RNA 1 [Gene - HGNC]
TTC21B:tetratricopeptide repeat domain 21B [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q24.3

Genomic location:

Preferred name:

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

HGVS:

NC_000002.12:g.165941111G>A
NG_030345.1:g.17728C>T
NM_024753.5:c.626C>TMANE SELECT
NP_079029.3:p.Pro209Leu
NC_000002.11:g.166797621G>A
NM_024753.3:c.626C>T
NM_024753.4:c.626C>T
Q7Z4L5:p.Pro209Leu
p.(Pro209Leu)

Protein change:

P209L; PRO209LEU

Links:

UniProtKB: Q7Z4L5#VAR_065518; OMIM: 612014.0001; dbSNP: rs140511594

NCBI 1000 Genomes Browser:

rs140511594

Molecular consequence:

NM_024753.5:c.626C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Nephronophthisis 12 (NPHP12)
Identifiers:: MONDO: MONDO:0013442; MedGen: C3151186; Orphanet: 655; OMIM: 613820

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000045215	OMIM	no assertion criteria provided	Pathogenic (Mar 1, 2011)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000693904	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard - Broad Institute Center for Mendelian Genomics (CMG)	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 26, 2017)	germline	research	PubMed (3) [See all records that cite these PMIDs] 24876116, 26940125, 25741868
SCV000965772	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	criteria provided, single submitter (ACMG Guidelines, 2007)	Pathogenic (Jan 1, 2015)	inherited	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001425282	Molecular Biology Laboratory, Fundació Puigvert - KidneyPanel_2020	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 1, 2020)	inherited	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 33532864
SCV003935133	Eurofins-Biomnis	criteria provided, single submitter (Accession Criteria ClinVar Biomnis)	Pathogenic (Dec 1, 2022)	biparental	clinical testing	Citation Link,
SCV004024139	Genomics And Bioinformatics Analysis Resource, Columbia University	no assertion criteria provided	Pathogenic	unknown	research

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	biparental	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	inherited	yes	not provided	2	not provided	not provided	not provided	clinical testing, research
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	research
Caucasian	germline	yes	1	1	not provided	not provided	not provided	research

Citations

PubMed

TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum.

Davis EE, Zhang Q, Liu Q, Diplas BH, Davey LM, Hartley J, Stoetzel C, Szymanska K, Ramaswami G, Logan CV, Muzny DM, Young AC, Wheeler DA, Cruz P, Morgan M, Lewis LR, Cherukuri P, Maskeri B, Hansen NF, Mullikin JC, Blakesley RW, Bouffard GG; et al.

Nat Genet. 2011 Mar;43(3):189-96. doi: 10.1038/ng.756. Epub 2011 Jan 23.

PubMed [citation]

PMID:: 21258341
PMCID:: PMC3071301

A homozygous missense mutation in the ciliary gene TTC21B causes familial FSGS.

Huynh Cong E, Bizet AA, Boyer O, Woerner S, Gribouval O, Filhol E, Arrondel C, Thomas S, Silbermann F, Canaud G, Hachicha J, Ben Dhia N, Peraldi MN, Harzallah K, Iftene D, Daniel L, Willems M, Noel LH, Bole-Feysot C, Nitschké P, Gubler MC, Mollet G, et al.

J Am Soc Nephrol. 2014 Nov;25(11):2435-43. doi: 10.1681/ASN.2013101126. Epub 2014 May 29.

PubMed [citation]

PMID:: 24876116
PMCID:: PMC4214529

See all PubMed Citations (6)

Details of each submission

From OMIM, SCV000045215.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In affected members of 2 unrelated consanguineous families with nephronophthisis-12 (NPHP12; 613820), Davis et al. (2011) identified a homozygous mutation in exon 6 of the TTC21B gene, resulting in a pro209-to-leu (P209L) substitution in a TPR domain. One family was of Portuguese and the other of Egyptian descent. The mutation was not found in 796 controls. In vitro and in vivo functional expression studies in mammalian cells and zebrafish indicated that the mutant protein was a hypomorphic allele. In 2 additional families with early-onset NPHP with extrarenal manifestations, the P209L allele was found in compound heterozygosity with another pathogenic TTC21B allele: a cys552-to-ter (C552X; 612014.0002) substitution in exon 13 and an A-to-G transition in intron 20 (612014.0003), respectively. Both of the latter mutations were shown by expression studies to be functionally null alleles. Haplotype analysis indicated a founder effect for the P209L allele.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard - Broad Institute Center for Mendelian Genomics (CMG), SCV000693904.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	1	not provided	not provided	research	PubMed (3)

Description

Previously reported homozygous missense mutation (p.P209L) in the TTC21B gene in seven families with FSGS (PMID: 26940125).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	1	not provided

From Equipe Genetique des Anomalies du Developpement, Université de Bourgogne, SCV000965772.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Molecular Biology Laboratory, Fundació Puigvert - KidneyPanel_2020, SCV001425282.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	not provided	not provided	not provided		not provided	not provided	2	not provided

From Eurofins-Biomnis, SCV003935133.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	biparental	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Genomics And Bioinformatics Analysis Resource, Columbia University, SCV004024139.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 6, 2024

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