VCV000002529.5 - ClinVar

NM_144596.4(TTC8):c.1049+2_1049+4del

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(3)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_144596.4(TTC8):c.1049+2_1049+4del

Variation ID: 2529 Accession: VCV000002529.5

Type and length

Deletion, 3 bp

Location

Cytogenetic: 14q31.3 14: 88870200-88870202 (GRCh38) [ NCBI UCSC ] 14: 89336544-89336546 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 20, 2014	Feb 14, 2024	Jul 10, 2017

HGVS

Nucleotide	Protein	Molecular consequence
NM_144596.4:c.1049+2_1049+4del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_001288781.1:c.1097+2_1097+4del		splice donor
NM_001288782.1:c.455+2_455+4del		splice donor
NM_001288783.1:c.332+2_332+4del		splice donor
NM_001366535.2:c.1019+2_1019+4del		splice donor
NM_001366536.2:c.929+2_929+4del		splice donor
NM_198309.3:c.1019+2_1019+4del		splice donor
NM_198309.3:c.1019+2_1019+4delTGC
NM_198310.3:c.929+2_929+4del		splice donor
NC_000014.9:g.88870200_88870202del
NC_000014.8:g.89336544_89336546del
NG_008126.2:g.51048_51050del

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000014.9:88870199:TGC:

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Links

ClinGen: CA252322 OMIM: 608132.0002 dbSNP: rs587777807 VarSome

Comment on variant

NCBI staff reviewed the sequence information reported in PubMed 14520415 Supplementary Fig. 2a to determine the location of this allele on the current reference sequence.

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
TTC8		-	-	GRCh38 GRCh37	526	555

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Bardet-Biedl syndrome 8	Pathogenic (2)	criteria provided, single submitter	-	RCV000002638.6
Bardet-Biedl syndrome	Pathogenic (1)	criteria provided, single submitter	Jul 10, 2017	RCV000546783.5

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bardet-Biedl syndrome 8 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004101462.1 First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023	Comment: The splice site c.1049+2_1049+4del variant has been reported to segregate with Bardet-Biedl syndrome in a family (Ansley SJ et al., 2003). The variant is novel … (more) The splice site c.1049+2_1049+4del variant has been reported to segregate with Bardet-Biedl syndrome in a family (Ansley SJ et al., 2003). The variant is novel (not in any individuals) in 1000 Genomes and in 0.0004% alleles in heterozygous state in gnomAD. This variant has been reported to the ClinVar database as Pathogenic. Loss of function variants have been previously reported to be disease causing. Loss of function variants in TTC8 are known to be pathogenic (Janssen S et al., 2011). For these reasons, this variant has been classified as Pathogenic. The observed variant was also detected in heterozygous state in his parents and homozygous state in his sibling. (less) Clinical Features: Obesity (present) , Hypogonadism (present) , Myopia (present)
Pathogenic (Jul 10, 2017)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Bardet-Biedl syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000636547.4 First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 16199547‚ 16308660‚ 21052717‚ 14520415 Comment: For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: … (more) For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TTC8 are known to be pathogenic (PMID: 16308660, 21052717). This variant has been reported to segregate with Bardet-Biedl syndrome in a family (PMID: 14520415). ClinVar contains an entry for this variant (Variation ID: 2529). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 11 of the TTC8 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. (less)
Pathogenic (Oct 09, 2003)	no assertion criteria provided Method: literature only	BARDET-BIEDL SYNDROME 8 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000022796.2 First in ClinVar: Apr 04, 2013 Last updated: Oct 20, 2014	Publications: PubMed (1) PubMed: 14520415 Comment on evidence: In a consanguineous Pakistani family with Bardet-Biedl syndrome (BBS8; 615985), Ansley et al. (2003) identified a homozygous 3-bp deletion that abolished the donor sequence at … (more) In a consanguineous Pakistani family with Bardet-Biedl syndrome (BBS8; 615985), Ansley et al. (2003) identified a homozygous 3-bp deletion that abolished the donor sequence at the splice junction of exon 10 (IVS10+2-4delTGC) in all 3 patients, but not their unaffected sister. The authors predicted this mutation to result in a read-through culminating in an intronic stop codon. RT-PCR detected no TTC8 expression in cultured renal tubular cells and skin fibroblasts from 2 affected sibs, but detected expression in cells from their unaffected sister, who was heterozygous for the mutation, and in a control cell line. One of the affected sibs manifested situs inversus, which was not thought to be coincidental but to represent a defect of randomization of left-right symmetry. (less)

Comment:

The splice site c.1049+2_1049+4del variant has been reported to segregate with Bardet-Biedl syndrome in a family (Ansley SJ et al., 2003). The variant is novel (not in any individuals) in 1000 Genomes and in 0.0004% alleles in heterozygous state in gnomAD. This variant has been reported to the ClinVar database as Pathogenic. Loss of function variants have been previously reported to be disease causing. Loss of function variants in TTC8 are known to be pathogenic (Janssen S et al., 2011). For these reasons, this variant has been classified as Pathogenic. The observed variant was also detected in heterozygous state in his parents and homozygous state in his sibling.

Comment:

For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TTC8 are known to be pathogenic (PMID: 16308660, 21052717). This variant has been reported to segregate with Bardet-Biedl syndrome in a family (PMID: 14520415). ClinVar contains an entry for this variant (Variation ID: 2529). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 11 of the TTC8 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Mutation analysis in Bardet-Biedl syndrome by DNA pooling and massively parallel resequencing in 105 individuals.	Janssen S	Human genetics	2011	PMID: 21052717
BBS8 is rarely mutated in a cohort of 128 Bardet-Biedl syndrome families.	Stoetzel C	Journal of human genetics	2006	PMID: 16308660
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547
Basal body dysfunction is a likely cause of pleiotropic Bardet-Biedl syndrome.	Ansley SJ	Nature	2003	PMID: 14520415

Text-mined citations for rs587777807 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_144596.4(TTC8):c.1049+2_1049+4del

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs587777807 ...