NM_024753.5(TTC21B):c.2258C>T (p.Pro753Leu) AND Meckel-Gruber-like syndrome

Germline classification:: Benign (1 submission)
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001258267.2

Allele description [Variation Report for NM_024753.5(TTC21B):c.2258C>T (p.Pro753Leu)]

NM_024753.5(TTC21B):c.2258C>T (p.Pro753Leu)

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.2258C>T (p.Pro753Leu)

HGVS:

NC_000002.12:g.165912578G>A
NG_030345.1:g.46261C>T
NM_024753.5:c.2258C>TMANE SELECT
NP_079029.3:p.Pro753Leu
NC_000002.11:g.166769088G>A
NM_024753.4:c.2258C>T

Protein change:

P753L

Links:

dbSNP: rs539769126

NCBI 1000 Genomes Browser:

rs539769126

Molecular consequence:

NM_024753.5:c.2258C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Meckel-Gruber-like syndrome
Identifiers:

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001435190	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign	germline	research	PubMed (2) [See all records that cite these PMIDs] 21258341, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001435190

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

criteria provided, single submitter

(ACMG Guidelines, 2015)

Benign

germline

research

PubMed (2)
[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	yes	not provided	not provided	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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001435190.1

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

Description

The heterozygous p.Pro753Leu variant in TTC21B has been identified in 2 individuals with Meckel-Gruber-like syndrome (PMID: 21258341), but has also been identified in 5 unaffected individuals (PMID: 21258341), and >1% of South Asian chromosomes and 2 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the p.Pro753Leu variant may silghtly impact protein function (PMID: 21258341). However, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as benign for autosomal recessive Meckel-Gruber-like syndrome.

#	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		not provided	not provided	not provided	not provided

Last Updated: Apr 7, 2025

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