NM_024753.5(TTC21B):c.2587C>T (p.Arg863Trp) AND Asphyxiating thoracic dystrophy 4

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: May 6, 2021
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:: RCV000398651.16

Allele description [Variation Report for NM_024753.5(TTC21B):c.2587C>T (p.Arg863Trp)]

NM_024753.5(TTC21B):c.2587C>T (p.Arg863Trp)

Gene:

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.2587C>T (p.Arg863Trp)

HGVS:

NC_000002.12:g.165901892G>A
NG_030345.1:g.56947C>T
NM_024753.5:c.2587C>TMANE SELECT
NP_079029.3:p.Arg863Trp
NC_000002.11:g.166758402G>A
NM_024753.4:c.2587C>T

Protein change:

R863W

Links:

dbSNP: rs34489989

NCBI 1000 Genomes Browser:

rs34489989

Molecular consequence:

NM_024753.5:c.2587C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Asphyxiating thoracic dystrophy 4 (SRTD4)
Synonyms:: SHORT-RIB THORACIC DYSPLASIA 4 WITH OR WITHOUT POLYDACTYLY; SHORT-RIB THORACIC DYSPLASIA 4
Identifiers:: MONDO: MONDO:0013441; MedGen: C3151185; Orphanet: 474; OMIM: 613819

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000417621	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Jan 13, 2018)	germline	clinical testing	Citation Link,
SCV002768378	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 6, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 24876116, 21258341, 22773737, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000417621

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Jan 13, 2018)

germline

clinical testing

Citation Link,

SCV002768378

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(May 6, 2021)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

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

See all PubMed Citations (4)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000417621.3

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

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002768378.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with nephronophthisis 12 (MIM#613820), short-rib thoracic dysplasia 4 with or without polydactyly (MIM#613819) and familial focal segmental glomerulosclerosis (FSGS). Partial loss of function has also been described, and associated with hypomorphic variants in this gene (OMIM, PMIDs: 24876116, 21258341). (I) 0106 - This gene is associated with autosomal recessive disease. Although OMIM refers to the association of this gene with autosomal dominant nephronophthisis 12 (MIM#613820), no specific evidence was found in the literature confirming this observation. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 237 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (p.R863Q: 11 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated TPR-repeat motif (UniProt). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been classified as a variant of uncertain significance by clinical diagnostic laboratories and is heterozygous in one individual with autosomal recessive Bardet-Biedl syndrome, with no classification provided (ClinVar, PMID: 22773737). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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

Last Updated: Apr 20, 2025

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