VCV000642279.12 - ClinVar

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

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Likely pathogenic(4); Uncertain significance(2)

6 out of 6 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 642279 Accession: VCV000642279.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p21 2: 47021902 (GRCh38) [ NCBI UCSC ] 2: 47249041 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Aug 14, 2019	Jun 22, 2025	May 12, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_020458.4:c.1433T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_065191.2:p.Leu478Pro	missense
NM_001288951.2:c.1433T>C	NP_001275880.1:p.Leu478Pro	missense
NM_001288953.2:c.1331T>C	NP_001275882.1:p.Leu444Pro	missense
NM_001288955.2:c.371T>C	NP_001275884.1:p.Leu124Pro	missense
NC_000002.12:g.47021902T>C
NC_000002.11:g.47249041T>C
NG_034143.2:g.110774T>C
LRG_1323:g.110774T>C
LRG_1323t1:c.1433T>C	LRG_1323p1:p.Leu478Pro

... more HGVS ... less HGVS

Protein change

L124P, L444P, L478P

Other names

Canonical SPDI

NC_000002.12:47021901:T:C

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00020 (C)

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

The Genome Aggregation Database (gnomAD) 0.00002

The Genome Aggregation Database (gnomAD) 0.00003

Trans-Omics for Precision Medicine (TOPMed) 0.00004

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Links

ClinGen: CA1647666 dbSNP: rs201100272 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
TTC7A		Gene associated with autosomal recessive phenotype	No evidence available	GRCh38 GRCh37	1102	1277

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Multiple gastrointestinal atresias	Conflicting classifications of pathogenicity (3)	criteria provided, conflicting classifications	Aug 23, 2022	RCV000795715.11
not provided	Likely pathogenic (1)	criteria provided, single submitter	May 11, 2022	RCV002245672.2
Gastrointestinal defects and immunodeficiency syndrome 1	Likely pathogenic (1)	criteria provided, single submitter	Mar 13, 2024	RCV005029459.1
not specified	Uncertain significance (1)	criteria provided, single submitter	May 12, 2025	RCV005418350.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Aug 23, 2022) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Multiple gastrointestinal atresias	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000935185.3 First in ClinVar: Aug 14, 2019 Last updated: Feb 07, 2023	Publications: PubMed (1) PubMed: 25174867 Comment: show 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. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (Dec 18, 2019) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Gastrointestinal defects and immunodeficiency syndrome 1	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology Study: CSER-SouthSeq Accession: SCV001190495.1 First in ClinVar: Mar 26, 2020 Last updated: Mar 26, 2020	Comment: show ACMG codes: PM2, PM3, PP3, PP4 (less) Observation: 1 Collection method: research Allele origin: unknown Affected status: yes more Observation 1 Collection method: research Allele origin: unknown Affected status: yes Number of individuals with the variant: 1 Clinical Features: Failure to thrive in infancy (present) , Chronic diarrhea (present) , Neonatal hypoglycemia (present) , Bloody diarrhea (present) , Bloody mucoid diarrhea (present) , Colitis (present)

Likely pathogenic (Dec 16, 2019) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Gastrointestinal defects and immunodeficiency syndrome 1	Baylor Genetics Accession: SCV001520481.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: show This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: yes Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: yes

Likely pathogenic (May 11, 2022) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Not Provided	GeneDx Accession: SCV002513646.2 First in ClinVar: May 21, 2022 Last updated: Mar 04, 2023	Comment: show Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25174867, 31787977) (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Likely pathogenic (Mar 13, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Gastrointestinal defects and immunodeficiency syndrome 1	Fulgent Genetics, Fulgent Genetics Accession: SCV005661081.1 First in ClinVar: Jan 25, 2025 Last updated: Jan 25, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (May 12, 2025) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	not specified	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV006086948.1 First in ClinVar: Jun 22, 2025 Last updated: Jun 22, 2025	Publications: PubMed (2) PubMed: 34930662‚ 25174867 Comment: show Variant summary: TTC7A c.1433T>C (p.Leu478Pro) results in a non-conservative amino acid change in the encoded protein sequence. 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. The variant allele was found at a frequency of 1.2e-05 in 251438 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1433T>C has been observed in an individual(s) affected with features of Gastrointestinal Defects And Immunodeficiency Syndrome (e.g., Lemoine_2014). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25174867, 34930662). ClinVar contains an entry for this variant (Variation ID: 642279). Based on the evidence outlined above, the variant was classified as uncertain significance. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

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.

Comment:

Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25174867, 31787977)

Comment:

Variant summary: TTC7A c.1433T>C (p.Leu478Pro) results in a non-conservative amino acid change in the encoded protein sequence. 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. The variant allele was found at a frequency of 1.2e-05 in 251438 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1433T>C has been observed in an individual(s) affected with features of Gastrointestinal Defects And Immunodeficiency Syndrome (e.g., Lemoine_2014). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25174867, 34930662). ClinVar contains an entry for this variant (Variation ID: 642279). Based on the evidence outlined above, the variant was classified as uncertain significance.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Genome sequencing as a first-line diagnostic test for hospitalized infants.	Bowling KM	Genetics in medicine : official journal of the American College of Medical Genetics	2022	PMID: 34930662
Immune deficiency-related enteropathy-lymphocytopenia-alopecia syndrome results from tetratricopeptide repeat domain 7A deficiency.	Lemoine R	The Journal of allergy and clinical immunology	2014	PMID: 25174867

Text-mined citations for rs201100272 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Dec 14, 2025