NM_001329943.3(KIAA0586):c.392del (p.Arg131fs) AND multiple conditions

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Jan 30, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000652578.19

Allele description [Variation Report for NM_001329943.3(KIAA0586):c.392del (p.Arg131fs)]

NM_001329943.3(KIAA0586):c.392del (p.Arg131fs)

Gene:

KIAA0586:KIAA0586 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

14q23.1

Genomic location:

Preferred name:

NM_001329943.3(KIAA0586):c.392del (p.Arg131fs)

Other names:

NM_001329943.3(KIAA0586):c.392del; p.Arg131fs

HGVS:

NC_000014.9:g.58432439del
NG_051335.2:g.10055del
NM_001244189.2:c.428del
NM_001244190.2:c.347del
NM_001244191.2:c.137del
NM_001244192.2:c.137del
NM_001329943.3:c.392delMANE SELECT
NM_001329944.2:c.392del
NM_001329945.2:c.137del
NM_001329946.2:c.392del
NM_001329947.2:c.392del
NM_001364700.1:c.137del
NM_001364701.2:c.137del
NM_014749.5:c.392del
NP_001231118.1:p.Arg143fs
NP_001231119.1:p.Arg116fs
NP_001231120.1:p.Arg46fs
NP_001231121.1:p.Arg46fs
NP_001316872.1:p.Arg131fs
NP_001316873.1:p.Arg131fs
NP_001316874.1:p.Arg46fs
NP_001316875.1:p.Arg131fs
NP_001316876.1:p.Arg131fs
NP_001351629.1:p.Arg46fs
NP_001351630.1:p.Arg46fs
NP_055564.3:p.Arg131fs
LRG_1096t1:c.428del
LRG_1096t2:c.392del
LRG_1096t3:c.392del
LRG_1096:g.10055del
LRG_1096p1:p.Arg143fs
LRG_1096p2:p.Arg131fs
LRG_1096p3:p.Arg131fs
NC_000014.8:g.58899157del
NC_000014.8:g.58899157delG
NM_001244189.1:c.428del
NM_001244189.1:c.428delG
NM_001244190.1:c.347delG
NM_001329943.2:c.392del
NM_001329943.3:c.392del
NM_014749.3:c.392del
p.Arg143LysfsX4

Protein change:

R116fs

Links:

OMIM: 610178.0001; dbSNP: rs534542684

NCBI 1000 Genomes Browser:

rs534542684

Molecular consequence:

NM_001244189.2:c.428del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001244190.2:c.347del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001244191.2:c.137del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001244192.2:c.137del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001329943.3:c.392del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001329944.2:c.392del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001329945.2:c.137del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001329946.2:c.392del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001329947.2:c.392del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001364700.1:c.137del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001364701.2:c.137del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_014749.5:c.392del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Name:: Joubert syndrome 23 (JBTS23)
Identifiers:: MONDO: MONDO:0014664; MedGen: C4084822; Orphanet: 475; OMIM: 616490

Name:: Short-rib thoracic dysplasia 14 with polydactyly (SRTD14)
Identifiers:: MONDO: MONDO:0014688; MedGen: C4225286; Orphanet: 397715; OMIM: 616546

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000774448	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 30, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 26166481, 26386044, 26026149, 26096313, 26386247, 26437029, 30120217, 28492532
SCV001251483	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill - NSIGHT-NC NEXUS	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	germline	research	PubMed (8) [See all records that cite these PMIDs] 29068549, 28125082, 26026149, 26096313, 26386044, 26386247, 30120217, 25741868
SCV002061501	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 18, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002097735	New York Genome Center - CSER-NYCKidSeq	criteria provided, single submitter (NYGC Assertion Criteria 2020)	Pathogenic (Oct 23, 2021)	inherited, germline	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	inherited	unknown	2	not provided	not provided	2	not provided	clinical testing
not provided	germline	no	1	not provided	not provided	not provided	not provided	research
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Mutations in KIAA0586 Cause Lethal Ciliopathies Ranging from a Hydrolethalus Phenotype to Short-Rib Polydactyly Syndrome.

Alby C, Piquand K, Huber C, Megarbané A, Ichkou A, Legendre M, Pelluard F, Encha-Ravazi F, Abi-Tayeh G, Bessières B, El Chehadeh-Djebbar S, Laurent N, Faivre L, Sztriha L, Zombor M, Szabó H, Failler M, Garfa-Traore M, Bole C, Nitschké P, Nizon M, Elkhartoufi N, et al.

Am J Hum Genet. 2015 Aug 6;97(2):311-8. doi: 10.1016/j.ajhg.2015.06.003. Epub 2015 Jul 9.

PubMed [citation]

PMID:: 26166481
PMCID:: PMC4573270

Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families.

Akawi N, McRae J, Ansari M, Balasubramanian M, Blyth M, Brady AF, Clayton S, Cole T, Deshpande C, Fitzgerald TW, Foulds N, Francis R, Gabriel G, Gerety SS, Goodship J, Hobson E, Jones WD, Joss S, King D, Klena N, Kumar A, Lees M, et al.

Nat Genet. 2015 Nov;47(11):1363-9. doi: 10.1038/ng.3410. Epub 2015 Oct 5.

PubMed [citation]

PMID:: 26437029
PMCID:: PMC5988033

See all PubMed Citations (11)

Details of each submission

From Invitae, SCV000774448.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change creates a premature translational stop signal (p.Arg143Lysfs*4) in the KIAA0586 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KIAA0586 are known to be pathogenic (PMID: 26096313, 26166481, 26386044). This variant is present in population databases (rs534542684, gnomAD 0.8%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with Joubert syndrome (PMID: 26026149, 26096313, 26386247, 26437029, 30120217). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 204593). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill - NSIGHT-NC NEXUS, SCV001251483.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	PubMed (8)

Description

This variant has been reported in Joubert syndrome and in cases with overlapping features of Jeune syndrome, or short-rib thoracic dysplasia with polydactyly. The c.428delG variant is considered a mild or hypomorphic variant that only causes disease when inherited in trans with a more severe KIAA0586 mutation (PMID: 29068549; 28125082; 26026149; 26096313; 26386044, 26386247; 30120217).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		1	not provided	not provided	not provided

From Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center, SCV002061501.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

PVS1, PM3_strong

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From New York Genome Center - CSER-NYCKidSeq, SCV002097735.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided
2	not provided	1	not provided	not provided	clinical testing	not provided
3	not provided	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	unknown	1	not provided	not provided		1	not provided	not provided	not provided
2	inherited	unknown	1	not provided	not provided		1	not provided	not provided	not provided
3	germline	unknown	1	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Apr 20, 2024

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