NM_018718.3(CEP41):c.423-2A>C AND Joubert syndrome 15

Clinical significance:Pathogenic (Last evaluated: Oct 8, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000023825.5

Allele description [Variation Report for NM_018718.3(CEP41):c.423-2A>C]

NM_018718.3(CEP41):c.423-2A>C

Gene:
CEP41:centrosomal protein 41 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
7q32.2
Genomic location:
Preferred name:
NM_018718.3(CEP41):c.423-2A>C
HGVS:
  • NC_000007.14:g.130402801T>G
  • NG_032164.1:g.43410A>C
  • NG_032164.2:g.43410A>C
  • NM_001257158.2:c.423-2A>C
  • NM_001257159.1:c.375-2A>C
  • NM_018718.3:c.423-2A>CMANE SELECT
  • NC_000007.13:g.130042642T>G
  • NM_018718.2:c.423-2A>C
Note:
ClinGen staff contributed the HGVS expression for this variant.
Nucleotide change:
IVS6AS, A-C, -2
Links:
OMIM: 610523.0003; dbSNP: rs781815473
NCBI 1000 Genomes Browser:
rs781815473
Molecular consequence:
  • NM_001257158.2:c.423-2A>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001257159.1:c.375-2A>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_018718.3:c.423-2A>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
Observations:
1

Condition(s)

Name:
Joubert syndrome 15 (JBTS15)
Identifiers:
MONDO: MONDO:0013763; MedGen: C3280897; Orphanet: 475; OMIM: 614464

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000045116OMIMno assertion criteria providedPathogenic
(Jan 15, 2012)
germlineliterature only

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

SCV000996177Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diegocriteria provided, single submitter
Pathogenic
(Jul 23, 2018)
germlineclinical testing

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

SCV001587214Invitaecriteria provided, single submitter
Pathogenic
(Oct 8, 2020)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot provided1not providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]
PMID:
16199547
PMCID:
PMC1735933
See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000045116.2

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

Description

In a patient, born of consanguineous Portuguese parents, with Joubert syndrome (JBTS15; 614464), Lee et al. (2012) identified a homozygous A-to-C transversion (423-2A-C), predicted to abolish the splice acceptor site from exon 7. The patient had hypotonia, ataxia, mental retardation, retinopathy, polydactyly, and the molar tooth sign on brain imaging. He did not have renal or hepatic involvement. He was also found to carry a heterozygous mutation in the CEP290 gene (610142).

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

From Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV000996177.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)

Description

This variant affects the canonical splice acceptor site of intron 6 and is therefore predicted to interfere with splicing and result in loss of normal protein function. This variant has been previously reported as a homozygous change in a patient with Joubert Syndrome (PMID: 22246503). It is present in the heterozygous state in the gnomAD population database at 0.0008% (2/246208) and thus is presumed to be rare. In silico analyses support a deleterious effect of the c.423-2A>C variant on protein function. Based on the available evidence, the c.423-2A>C variant is classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not providednot provided1not providednot providednot provided

From Invitae, SCV001587214.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change affects an acceptor splice site in intron 6 of the CEP41 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs781815473, ExAC 0.001%). This variant has been observed in individual(s) with Joubert syndrome (PMID: 22246503). ClinVar contains an entry for this variant (Variation ID: 30840). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CEP41 are known to be pathogenic (PMID: 22246503). For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Oct 7, 2021

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