NM_052989.3(IFT122):c.3031G>C (p.Ala1011Pro) AND Cranioectodermal dysplasia 1

Clinical significance:Uncertain significance (Last evaluated: Jul 10, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV001219619.2

Allele description [Variation Report for NM_052989.3(IFT122):c.3031G>C (p.Ala1011Pro)]

NM_052989.3(IFT122):c.3031G>C (p.Ala1011Pro)

Gene:
IFT122:intraflagellar transport 122 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
3q22.1
Genomic location:
Preferred name:
NM_052989.3(IFT122):c.3031G>C (p.Ala1011Pro)
HGVS:
  • NC_000003.12:g.129514432G>C
  • NG_023392.1:g.79308G>C
  • NM_001280541.2:c.3010G>C
  • NM_001280545.2:c.2581G>C
  • NM_001280546.2:c.2404G>C
  • NM_018262.4:c.2854G>C
  • NM_052985.4:c.3184G>C
  • NM_052989.3:c.3031G>CMANE SELECT
  • NM_052990.3:c.2701G>C
  • NP_001267470.1:p.Ala1004Pro
  • NP_001267474.1:p.Ala861Pro
  • NP_001267475.1:p.Ala802Pro
  • NP_060732.2:p.Ala952Pro
  • NP_443711.2:p.Ala1062Pro
  • NP_443715.1:p.Ala1011Pro
  • NP_443716.1:p.Ala901Pro
  • NC_000003.11:g.129233275G>C
  • NM_052985.3:c.3184G>C
Protein change:
A1004P; ALA1062PRO
Links:
OMIM: 606045.0007
Molecular consequence:
  • NM_001280541.2:c.3010G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001280545.2:c.2581G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001280546.2:c.2404G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_018262.4:c.2854G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_052985.4:c.3184G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_052989.3:c.3031G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_052990.3:c.2701G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Cranioectodermal dysplasia 1 (CED1)
Synonyms:
LEVIN SYNDROME I; Levin syndrome 1
Identifiers:
MONDO: MONDO:0021093; MedGen: C0432235; Orphanet: 1515; OMIM: 218330

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001391567Invitaecriteria provided, single submitter
Uncertain significance
(Jul 10, 2019)
germlineclinical testing

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

SCV001441270OMIMno assertion criteria providedPathogenic
(Feb 1, 2011)
germlineliterature only

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

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

Mutation in IFT80 in a fetus with the phenotype of Verma-Naumoff provides molecular evidence for Jeune-Verma-Naumoff dysplasia spectrum.

Cavalcanti DP, Huber C, Sang KH, Baujat G, Collins F, Delezoide AL, Dagoneau N, Le Merrer M, Martinovic J, Mello MF, Vekemans M, Munnich A, Cormier-Daire V.

J Med Genet. 2011 Feb;48(2):88-92. doi: 10.1136/jmg.2009.069468. Epub 2009 Jul 30.

PubMed [citation]
PMID:
19648123
See all PubMed Citations (3)

Details of each submission

From Invitae, SCV001391567.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces alanine with proline at codon 1062 of the IFT122 protein (p.Ala1062Pro). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and proline. This variant is present in population databases (rs199622112, ExAC 0.02%). This variant has been observed in individuals affected with clinical features of short-rib thoracic dysplasia (PMID: 28370949, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From OMIM, SCV001441270.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (2)

Description

In a male infant who died shortly after birth with craniosynostosis, short ribs, micromelia, and postaxial polydactyly of the hands (CED1; 218330), who was previously studied by Cavalcanti et al. (2011), Silveira et al. (2017) identified 3 mutations in the IFT122 gene: a c.3184G-C transversion, resulting in an ala1062-to-pro (A1062P) substitution within the tetratricopeptide-like helical domain, on 1 allele; and a 1-bp duplication (c.3228dupG) followed by 3-bp deletion (c.3231_3233delCAT) on the other allele (606045.0008), predicted to result in a premature termination codon (Tyr1077ValfsTer10). The complex mutation was inherited from his unaffected mother; DNA was unavailable from the father. The A1062P variant was not found in 100 control chromosomes, but was present at low frequency (0.00002479) in the ExAC database, only in heterozygosity.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

Last Updated: Apr 12, 2021

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