NM_020458.4(TTC7A):c.1433T>C (p.Leu478Pro) AND Multiple gastrointestinal atresias

Germline classification:: Conflicting classifications of pathogenicity (3 submissions)
Last evaluated:: Aug 23, 2022
Review status:: criteria provided, conflicting classifications

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:: RCV000795715.11

Allele description [Variation Report for NM_020458.4(TTC7A):c.1433T>C (p.Leu478Pro)]

NM_020458.4(TTC7A):c.1433T>C (p.Leu478Pro)

Gene:

TTC7A:tetratricopeptide repeat domain 7A [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p21

Genomic location:

Preferred name:

NM_020458.4(TTC7A):c.1433T>C (p.Leu478Pro)

HGVS:

NC_000002.12:g.47021902T>C
NG_034143.2:g.110774T>C
NM_001288951.2:c.1433T>C
NM_001288953.2:c.1331T>C
NM_001288955.2:c.371T>C
NM_020458.4:c.1433T>CMANE SELECT
NP_001275880.1:p.Leu478Pro
NP_001275882.1:p.Leu444Pro
NP_001275884.1:p.Leu124Pro
NP_065191.2:p.Leu478Pro
LRG_1323t1:c.1433T>C
LRG_1323:g.110774T>C
LRG_1323p1:p.Leu478Pro
NC_000002.11:g.47249041T>C
NG_034143.1:g.110774T>C
NM_001288951.1:c.1433T>C
NM_020458.2:c.1433T>C
NM_020458.3:c.1433T>C

Protein change:

L124P

Links:

dbSNP: rs201100272

NCBI 1000 Genomes Browser:

rs201100272

Molecular consequence:

NM_001288951.2:c.1433T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001288953.2:c.1331T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001288955.2:c.371T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_020458.4:c.1433T>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Multiple gastrointestinal atresias
Synonyms:: FAMILIAL INTESTINAL POLYATRESIA SYNDROME; Multiple intestinal atresia
Identifiers:: MONDO: MONDO:0009465; MedGen: C0220744; Orphanet: 2300

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000935185	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 23, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25174867, 28492532
SCV001190495	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-SouthSeq	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 18, 2019)	unknown	research	PubMed (1) [See all records that cite this PMID]
SCV001520481	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 16, 2019)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000935185

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 23, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV001190495

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-SouthSeq

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Dec 18, 2019)

unknown

research

PubMed (1)
[See all records that cite this PMID]

SCV001520481

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Dec 16, 2019)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

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
not provided	unknown	yes	1	not provided	not provided	1	not provided	clinical testing, research

Citations

PubMed

Immune deficiency-related enteropathy-lymphocytopenia-alopecia syndrome results from tetratricopeptide repeat domain 7A deficiency.

Lemoine R, Pachlopnik-Schmid J, Farin HF, Bigorgne A, Debré M, Sepulveda F, Héritier S, Lemale J, Talbotec C, Rieux-Laucat F, Ruemmele F, Morali A, Cathebras P, Nitschke P, Bole-Feysot C, Blanche S, Brousse N, Picard C, Clevers H, Fischer A, de Saint Basile G.

J Allergy Clin Immunol. 2014 Dec;134(6):1354-1364.e6. doi: 10.1016/j.jaci.2014.07.019. Epub 2014 Aug 28.

PubMed [citation]

PMID:: 25174867

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. doi: 10.1038/s41436-019-0624-9..

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000935185.3

#	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 leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 478 of the TTC7A protein (p.Leu478Pro). This variant is present in population databases (rs201100272, gnomAD 0.003%). This missense change has been observed in individual(s) with inflammatory bowel disease and primary immune defects (PMID: 25174867). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 642279). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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

From HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-SouthSeq, SCV001190495.1

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

Description

ACMG codes: PM2, PM3, PP3, PP4

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

From Baylor Genetics, SCV001520481.1

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

Description

This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

#	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 7, 2025

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