VCV000406217.17 - ClinVar

NM_020800.3(IFT80):c.1093A>G (p.Thr365Ala)

Germline

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.

(7)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Pathogenic(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_020800.3(IFT80):c.1093A>G (p.Thr365Ala)

Variation ID: 406217 Accession: VCV000406217.17

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3q25.33 3: 160303973 (GRCh38) [ NCBI UCSC ] 3: 160021761 (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	Apr 17, 2017	Oct 8, 2024	Jan 19, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_020800.3:c.1093A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_065851.1:p.Thr365Ala	missense
NM_001190241.2:c.682A>G	NP_001177170.1:p.Thr228Ala	missense
NM_001190242.2:c.682A>G	NP_001177171.1:p.Thr228Ala	missense
NR_148401.1:n.1801A>G		non-coding transcript variant
NR_148402.1:n.3337A>G		non-coding transcript variant
NR_148403.1:n.3604A>G		non-coding transcript variant
NC_000003.12:g.160303973T>C
NC_000003.11:g.160021761T>C
NG_022932.1:g.100560A>G

... more HGVS ... less HGVS

Protein change

T365A, T228A

Other names

Canonical SPDI

NC_000003.12:160303972:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

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) 0.00006

The Genome Aggregation Database (gnomAD), exomes 0.00006

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

The Genome Aggregation Database (gnomAD) 0.00023

Trans-Omics for Precision Medicine (TOPMed) 0.00028

Links

ClinGen: CA2685255 dbSNP: rs140202230 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.
IFT80		-	-	GRCh38 GRCh37	11	651
TRIM59-IFT80	-	-	-	GRCh38	-	726

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.
Jeune thoracic dystrophy	Pathogenic (3)	criteria provided, single submitter	Jan 19, 2024	RCV000465513.8
Type IV short rib polydactyly syndrome	Pathogenic/Likely pathogenic (2)	no assertion criteria provided	Jun 1, 2017	RCV000515813.2
Asphyxiating thoracic dystrophy 2	Uncertain significance (1)	criteria provided, single submitter	May 4, 2023	RCV001803759.8
IFT80-related disorder	Likely pathogenic (1)	no assertion criteria provided	Jul 12, 2024	RCV003942476.2

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.	More information 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.
Pathogenic (Jan 19, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Jeune thoracic dystrophy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000544759.5 First in ClinVar: Apr 17, 2017 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 29068549 Comment: This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 365 of the IFT80 protein (p.Thr365Ala). … (more) This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 365 of the IFT80 protein (p.Thr365Ala). This variant is present in population databases (rs140202230, gnomAD 0.09%). This missense change has been observed in individual(s) with clinical features of short-rib polydactyly syndrome or asphyxiating thoracic dystrophy (PMID: 29068549; Invitae; external communication). 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: 406217). 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) performed at Invitae indicates that this missense variant is not expected to disrupt IFT80 protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. (less)
Uncertain significance (May 04, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	Asphyxiating thoracic dystrophy 2 Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV002048912.2 First in ClinVar: Jan 08, 2022 Last updated: Feb 20, 2024	Comment: The IFT80 c.1093A>G; p.Thr365Ala variant (rs140202230) was reported as compound heterozygous with another disease-associated variant in two individuals affected with short-rib polydactyly syndrome type IV … (more) The IFT80 c.1093A>G; p.Thr365Ala variant (rs140202230) was reported as compound heterozygous with another disease-associated variant in two individuals affected with short-rib polydactyly syndrome type IV or asphyxiating thoracic dystrophy (Zhang 2018). However, phasing was not confirmed in these reports. This variant is also reported in ClinVar (Variation ID: 406217) and is found in the general population with an overall allele frequency of 0.008% (23/282,476 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.492). However, given the lack of clinical and functional data, the significance of the p.Thr365Ala variant is uncertain at this time. References: Zhang et al. Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies. Hum Mutat. 2018 Jan;39(1):152-166. PMID: 29068549. (less)
Pathogenic (Jun 01, 2017)	no assertion criteria provided Method: research	Asphyxiating thoracic dystrophy Affected status: yes Allele origin: unknown	Dan Cohn Lab, University Of California Los Angeles Accession: SCV000612066.1 First in ClinVar: Apr 17, 2017 Last updated: Apr 17, 2017	Publications: PubMed (1) PubMed: 29068549
Pathogenic (Jun 01, 2017)	no assertion criteria provided Method: research	Type IV short rib polydactyly syndrome Affected status: yes Allele origin: unknown	Dan Cohn Lab, University Of California Los Angeles Accession: SCV000612068.1 First in ClinVar: Dec 10, 2017 Last updated: Dec 10, 2017	Publications: PubMed (1) PubMed: 29068549
Likely pathogenic (-)	no assertion criteria provided Method: research	asphyxiating thoracic dystrophy Affected status: yes Allele origin: inherited	University of Washington Center for Mendelian Genomics, University of Washington Accession: SCV001479582.1 First in ClinVar: Feb 20, 2021 Last updated: Feb 20, 2021	Publications: PubMed (1) PubMed: 29068549
Likely pathogenic (-)	no assertion criteria provided Method: research	short-rib polydactyly syndrome type IV Affected status: yes Allele origin: inherited	University of Washington Center for Mendelian Genomics, University of Washington Accession: SCV001479584.1 First in ClinVar: Feb 20, 2021 Last updated: Feb 20, 2021	Publications: PubMed (1) PubMed: 29068549
Likely pathogenic (Jul 12, 2024)	no assertion criteria provided Method: clinical testing	IFT80-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004760732.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: The IFT80 c.1093A>G variant is predicted to result in the amino acid substitution p.Thr365Ala. This variant along with a second variant in the IFT80 gene … (more) The IFT80 c.1093A>G variant is predicted to result in the amino acid substitution p.Thr365Ala. This variant along with a second variant in the IFT80 gene has been reported in two patients with asphyxiating thoracic dystrophy and perinatal lethal short-rib polydactyly syndromes, respectively (Table S2, Zhang et al. 2018. PubMed ID: 29068549). This variant is reported in 0.092% of alleles in individuals of African descent in gnomAD. This variant is interpreted as likely pathogenic. (less)

Comment:

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 365 of the IFT80 protein (p.Thr365Ala). This variant is present in population databases (rs140202230, gnomAD 0.09%). This missense change has been observed in individual(s) with clinical features of short-rib polydactyly syndrome or asphyxiating thoracic dystrophy (PMID: 29068549; Invitae; external communication). 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: 406217). 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) performed at Invitae indicates that this missense variant is not expected to disrupt IFT80 protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.

Comment:

The IFT80 c.1093A>G; p.Thr365Ala variant (rs140202230) was reported as compound heterozygous with another disease-associated variant in two individuals affected with short-rib polydactyly syndrome type IV or asphyxiating thoracic dystrophy (Zhang 2018). However, phasing was not confirmed in these reports. This variant is also reported in ClinVar (Variation ID: 406217) and is found in the general population with an overall allele frequency of 0.008% (23/282,476 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.492). However, given the lack of clinical and functional data, the significance of the p.Thr365Ala variant is uncertain at this time. References: Zhang et al. Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies. Hum Mutat. 2018 Jan;39(1):152-166. PMID: 29068549.

Comment:

The IFT80 c.1093A>G variant is predicted to result in the amino acid substitution p.Thr365Ala. This variant along with a second variant in the IFT80 gene has been reported in two patients with asphyxiating thoracic dystrophy and perinatal lethal short-rib polydactyly syndromes, respectively (Table S2, Zhang et al. 2018. PubMed ID: 29068549). This variant is reported in 0.092% of alleles in individuals of African descent in gnomAD. This variant is interpreted as likely pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies.	Zhang W	Human mutation	2018	PMID: 29068549

Text-mined citations for rs140202230 ...

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 Oct 13, 2024

ClinVar Genomic variation as it relates to human health

NM_020800.3(IFT80):c.1093A>G (p.Thr365Ala)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs140202230 ...