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NM_001134831.2(AHI1):c.910dup (p.Thr304fs) AND Joubert syndrome 3

Clinical significance:Pathogenic (Last evaluated: Jul 15, 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:
RCV000201689.4

Allele description [Variation Report for NM_001134831.2(AHI1):c.910dup (p.Thr304fs)]

NM_001134831.2(AHI1):c.910dup (p.Thr304fs)

Gene:
AHI1:Abelson helper integration site 1 [Gene - OMIM - HGNC]
Variant type:
Duplication
Cytogenetic location:
6q23.3
Genomic location:
Preferred name:
NM_001134831.2(AHI1):c.910dup (p.Thr304fs)
HGVS:
  • NC_000006.12:g.135463153dup
  • NG_008643.2:g.39620dup
  • NM_001134830.2:c.910dup
  • NM_001134831.2:c.910dupMANE SELECT
  • NM_001134832.2:c.910dup
  • NM_001350503.2:c.910dup
  • NM_001350504.2:c.910dup
  • NM_017651.5:c.910dup
  • NP_001128302.1:p.Thr304fs
  • NP_001128302.1:p.Thr304fs
  • NP_001128303.1:p.Thr304fs
  • NP_001128304.1:p.Thr304fs
  • NP_001337432.1:p.Thr304fs
  • NP_001337433.1:p.Thr304fs
  • NP_060121.3:p.Thr304fs
  • NP_060121.3:p.Thr304fs
  • NC_000006.11:g.135784283_135784284insT
  • NC_000006.11:g.135784291dup
  • NM_001134830.1:c.910dup
  • NM_001134831.1:c.910dupA
  • NM_001134831.2:c.910dupAMANE SELECT
  • NM_017651.4:c.910dup
Protein change:
T304fs
Links:
dbSNP: rs753874898
NCBI 1000 Genomes Browser:
rs753874898
Molecular consequence:
  • NM_001134830.2:c.910dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001134831.2:c.910dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001134832.2:c.910dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001350503.2:c.910dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001350504.2:c.910dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_017651.5:c.910dup - frameshift variant - [Sequence Ontology: SO:0001589]
Functional consequence:
loss_of_function_variant [Sequence Ontology: SO:0002054]

Condition(s)

Name:
Joubert syndrome 3 (JBTS3)
Synonyms:
Joubert syndrome with ocular anomalies; AHI1-related Ciliopathy
Identifiers:
MONDO: MONDO:0012078; MedGen: C1837713; Orphanet: 220493; OMIM: 608629

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000256261UW Hindbrain Malformation Research Program,University of Washington

See additional submitters

criteria provided, single submitter
Pathogenic
(Feb 23, 2015)
unknownresearch

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

SCV001422498Breda Genetics srlcriteria provided, single submitter
Pathogenic
(Jul 15, 2020)
germlineclinical testing

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

SCV001443009Institute of Human Genetics, University of Leipzig Medical Centercriteria provided, single submitter
Pathogenic
(Mar 1, 2020)
biparentalclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedbiparentalyesnot providednot providednot providednot providednot providedclinical testing
not providedunknownyesnot providednot providednot providednot providednot providedresearch
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity.

Bachmann-Gagescu R, Dempsey JC, Phelps IG, O'Roak BJ, Knutzen DM, Rue TC, Ishak GE, Isabella CR, Gorden N, Adkins J, Boyle EA, de Lacy N, O'Day D, Alswaid A, Ramadevi A R, Lingappa L, Lourenço C, Martorell L, Garcia-Cazorla À, Ozyürek H, Haliloğlu G, Tuysuz B, et al.

J Med Genet. 2015 Aug;52(8):514-22. doi: 10.1136/jmedgenet-2015-103087. Epub 2015 Jun 19.

PubMed [citation]
PMID:
26092869
PMCID:
PMC5082428

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

Details of each submission

From UW Hindbrain Malformation Research Program,University of Washington, SCV000256261.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearch PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot providednot providednot providednot providednot provided

From Breda Genetics srl, SCV001422498.1

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

Description

The variant c.910dupA (p.Thr304Asnfs*6) is reported as pathogenic for Joubert syndrome 3 in ClinVar (Variation ID: 217536). The variant creates a shift in the reading frame which is predicted to result in a premature stop codon 6 amino acids downstream, which is likely to result in a truncated protein or protein loss due to nonsense-mediated messenger decay (NMD). The variant is present in gnomAD with an estimated allele frequency of 0.0001588, with no homozygous individuals reported. However, this variant was filtered out the gnomAD database because of it is found in a low complexity region and failed the random forest filters, due to presence of a poli-T stretch. Chafai-Elalaoui et al. (2015) reported the pathogenic variant c.910dupA (p.Thr304Asnfs*6) in the homozygous state in 3 affected sibling of a Moroccan family with Joubert syndrome (PMID: 26541515). The same mutation had already been reported by Kroes et al. (2008) in two Dutch patients in the compound heterozygous state (PMID: 18054307).

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

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001443009.1

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

Description

Review of the variants reported in Reuter et al., 2017, PMID: 28097321: PVS1,PM2,PM3

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

Last Updated: Jul 2, 2022

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