NM_024753.5(TTC21B):c.703G>C (p.Ala235Pro) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 13, 2023
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:: RCV001304507.4

Allele description [Variation Report for NM_024753.5(TTC21B):c.703G>C (p.Ala235Pro)]

NM_024753.5(TTC21B):c.703G>C (p.Ala235Pro)

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.703G>C (p.Ala235Pro)

HGVS:

NC_000002.12:g.165941034C>G
NG_030345.1:g.17805G>C
NM_024753.5:c.703G>CMANE SELECT
NP_079029.3:p.Ala235Pro
NC_000002.11:g.166797544C>G
NM_024753.4:c.703G>C

Protein change:

A235P

Links:

dbSNP: rs150742619

NCBI 1000 Genomes Browser:

rs150742619

Molecular consequence:

NM_024753.5:c.703G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Jeune thoracic dystrophy (ATD1)
Synonyms:: Jeune syndrome; Infantile thoracic dystrophy; Thoracic pelvic phalangeal dystrophy; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0018770; MedGen: C0265275; OMIM: PS208500

Name:: Nephronophthisis
Synonyms:: juvenile nephronophthisis
Identifiers:: MONDO: MONDO:0019005; MedGen: C0687120; OMIM: PS256100; Human Phenotype Ontology: HP:0000090

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001493792	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 13, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29068549, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001493792

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 13, 2023)

germline

clinical testing

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies.

Zhang W, Taylor SP, Ennis HA, Forlenza KN, Duran I, Li B, Sanchez JAO, Nevarez L, Nickerson DA, Bamshad M; University of Washington Center for Mendelian Genomics., Lachman RS, Krakow D, Cohn DH.

Hum Mutat. 2018 Jan;39(1):152-166. doi: 10.1002/humu.23362. Epub 2017 Nov 6.

PubMed [citation]

PMID:: 29068549
PMCID:: PMC6198324

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV001493792.4

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

Description

This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 235 of the TTC21B protein (p.Ala235Pro). This variant is present in population databases (rs150742619, gnomAD 0.02%). This missense change has been observed in individual(s) with asphyxiating thoracic dystrophy (PMID: 29068549). ClinVar contains an entry for this variant (Variation ID: 446647). Advanced 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 at Invitae 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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: Mar 5, 2024

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