NM_015189.3(EXOC6B):c.946del (p.Arg316fs) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Aug 10, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV002006372.7

Allele description [Variation Report for NM_015189.3(EXOC6B):c.946del (p.Arg316fs)]

NM_015189.3(EXOC6B):c.946del (p.Arg316fs)

Gene:

EXOC6B:exocyst complex component 6B [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

2p13.2

Genomic location:

Preferred name:

NM_015189.3(EXOC6B):c.946del (p.Arg316fs)

HGVS:

NC_000002.12:g.72515097del
NG_050967.1:g.315953del
NM_001321729.2:c.946del
NM_001321730.2:c.946del
NM_001321731.2:c.946del
NM_001321733.2:c.946del
NM_001321734.2:c.607del
NM_015189.2:c.946del
NM_015189.3:c.946delMANE SELECT
NP_001308658.1:p.Arg316fs
NP_001308659.1:p.Arg316fs
NP_001308660.1:p.Arg316fs
NP_001308662.1:p.Arg316fs
NP_001308663.1:p.Arg203fs
NP_056004.1:p.Arg316fs
NC_000002.11:g.72742225del
NC_000002.11:g.72742226del
NR_135773.2:n.1069del
NR_135774.2:n.1069del

Protein change:

R203fs

Links:

dbSNP: rs2105685436

NCBI 1000 Genomes Browser:

rs2105685436

Molecular consequence:

NM_001321729.2:c.946del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001321730.2:c.946del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001321731.2:c.946del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001321733.2:c.946del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001321734.2:c.607del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_015189.3:c.946del - frameshift variant - [Sequence Ontology: SO:0001589]
NR_135773.2:n.1069del - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_135774.2:n.1069del - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002270683	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 10, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 26669664, 36150098, 28492532
SCV003798726	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Jan 18, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002270683

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 10, 2023)

germline

clinical testing

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

SCV003798726

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Jan 18, 2022)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A novel multiple joint dislocation syndrome associated with a homozygous nonsense variant in the EXOC6B gene.

Girisha KM, Kortüm F, Shah H, Alawi M, Dalal A, Bhavani GS, Kutsche K.

Eur J Hum Genet. 2016 Aug;24(8):1206-10. doi: 10.1038/ejhg.2015.261. Epub 2015 Dec 16.

PubMed [citation]

PMID:: 26669664
PMCID:: PMC4970677

Biallelic loss-of-function variants in EXOC6B are associated with impaired primary ciliogenesis and cause spondylo-epi-metaphyseal dysplasia with joint laxity type 3.

Simsek-Kiper PO, Jacob P, Upadhyai P, Taşkıran ZE, Guleria VS, Karaosmanoglu B, Imren G, Gocmen R, Bhavani GS, Kausthubham N, Shah H, Utine GE, Boduroglu K, Girisha KM.

Hum Mutat. 2022 Dec;43(12):2116-2129. doi: 10.1002/humu.24478. Epub 2022 Oct 8. Review.

PubMed [citation]

PMID:: 36150098
PMCID:: PMC7615863

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002270683.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

ClinVar contains an entry for this variant (Variation ID: 1487322). For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with EXOC6B-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg316Glufs*22) in the EXOC6B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EXOC6B are known to be pathogenic (PMID: 26669664, 36150098).

#	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 GeneDx, SCV003798726.2

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

Description

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is not a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015)

#	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

Last Updated: Sep 29, 2024

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