The TULP1 c.1496-6C>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PS1, PM2, PM3, PP3. Based on this evidence we have classified this variant as Likely Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_003322.6(TULP1):c.1496-6C>A
Germline
Classification
Help
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.
(10)
Help
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/Likely pathogenic
10
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_003322.6(TULP1):c.1496-6C>A
Variation ID: 99666 Accession: VCV000099666.43
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6p21.31 6: 35498466 (GRCh38) [ NCBI UCSC ] 6: 35466243 (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 Feb 20, 2014 Oct 20, 2024 Nov 10, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_003322.6:c.1496-6C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001289395.2:c.1337-6C>A intron variant NC_000006.12:g.35498466G>T NC_000006.11:g.35466243G>T NG_009077.1:g.19405C>A - Protein change
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- Other names
- -
- Canonical SPDI
- NC_000006.12:35498465:G:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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Global minor allele
frequency (GMAF) HelpThe 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.
- -
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00009
The Genome Aggregation Database (gnomAD), exomes 0.00009
The Genome Aggregation Database (gnomAD) 0.00011
Trans-Omics for Precision Medicine (TOPMed) 0.00012
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| TULP1 | - | - |
GRCh38 GRCh37 |
785 | 795 | |
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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Nov 10, 2023 | RCV000086072.35 | |
| Likely pathogenic (2) |
criteria provided, single submitter
|
Apr 1, 2021 | RCV000787923.5 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Feb 15, 2019 | RCV001073440.4 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Apr 8, 2021 | RCV001376339.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 7, 2022 | RCV002228330.3 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Mar 4, 2022 | RCV002483168.3 |
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. |
|
|---|---|---|---|---|---|
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Likely pathogenic
(Feb 15, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Retinal dystrophy
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV001238982.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020
Comment:
My Retina Tracker patient
|
|
|
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Likely pathogenic
(Dec 02, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000332321.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
|
|
|
Likely pathogenic
(Apr 08, 2021)
|
criteria provided, single submitter
Method: research
|
Retinitis pigmentosa 14
Affected status: yes
Allele origin:
germline
|
Ocular Genomics Institute, Massachusetts Eye and Ear
Accession: SCV001573453.1
First in ClinVar: May 10, 2021 Last updated: May 10, 2021 |
Comment:
The TULP1 c.1496-6C>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we … (more)
The TULP1 c.1496-6C>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PS1, PM2, PM3, PP3. Based on this evidence we have classified this variant as Likely Pathogenic. (less)
|
|
|
Likely pathogenic
(Apr 01, 2021)
|
criteria provided, single submitter
Method: curation
|
Retinitis pigmentosa
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001950387.1
First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
Comment:
The c.1496-6C>A variant in TULP1 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics … (more)
The c.1496-6C>A variant in TULP1 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PS1, PM2, PM3, PP3. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. (less)
|
|
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Pathogenic
(Apr 07, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Leber congenital amaurosis
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002511666.1
First in ClinVar: May 16, 2022 Last updated: May 16, 2022 |
Comment:
Variant summary: TULP1 c.1496-6C>A alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered … (more)
Variant summary: TULP1 c.1496-6C>A alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. One computational tool predict a significant impact on normal splicing by abolishing a 3 prime acceptor site, while three predict the variant no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.8e-05 in 248766 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in TULP1 causing Leber Congenital Amaurosis (8.8e-05 vs 0.0005), allowing no conclusion about variant significance. c.1496-6C>A has been reported in the literature in multiple individuals affected with Retinitis pigmentosa or retinal degeneration. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (pathogenic/likely pathogenic n=6, VUS n=1). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
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Likely pathogenic
(Mar 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Retinitis pigmentosa 14
Leber congenital amaurosis 15
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002790257.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
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Pathogenic
(Nov 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001396695.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change falls in intron 14 of the TULP1 gene. It does not directly change the encoded amino acid sequence of the TULP1 protein. … (more)
This sequence change falls in intron 14 of the TULP1 gene. It does not directly change the encoded amino acid sequence of the TULP1 protein. This variant is present in population databases (rs281865171, gnomAD 0.02%). This variant has been observed in individual(s) with retinitis pigmentosa or cone-rod dystrophy (PMID: 9660588, 26766544, 28127548, 28981474). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 99666). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Likely pathogenic
(Nov 01, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV000780857.29
First in ClinVar: Feb 20, 2014 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 3
|
|
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Uncertain significance
(Apr 01, 2018)
|
no assertion criteria provided
Method: research
|
Retinitis pigmentosa
Affected status: yes
Allele origin:
unknown
|
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet
Study: VeluxRD
Accession: SCV000926942.2 First in ClinVar: Jul 21, 2019 Last updated: Sep 03, 2023 |
|
|
|
not provided
(-)
|
no classification provided
Method: not provided
|
not provided
Affected status: not provided
Allele origin:
not provided
|
Retina International
Accession: SCV000118216.1
First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014
Comment:
http://phencode.bx.psu.edu/cgi-bin/phencode/phencode?build=hg19&id=RISN_TULP1:c.1496-6C>A
|
|
Comment:
Comment:
The c.1496-6C>A variant in TULP1 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PS1, PM2, PM3, PP3. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
Comment:
Variant summary: TULP1 c.1496-6C>A alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. One computational tool predict a significant impact on normal splicing by abolishing a 3 prime acceptor site, while three predict the variant no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.8e-05 in 248766 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in TULP1 causing Leber Congenital Amaurosis (8.8e-05 vs 0.0005), allowing no conclusion about variant significance. c.1496-6C>A has been reported in the literature in multiple individuals affected with Retinitis pigmentosa or retinal degeneration. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (pathogenic/likely pathogenic n=6, VUS n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change falls in intron 14 of the TULP1 gene. It does not directly change the encoded amino acid sequence of the TULP1 protein. This variant is present in population databases (rs281865171, gnomAD 0.02%). This variant has been observed in individual(s) with retinitis pigmentosa or cone-rod dystrophy (PMID: 9660588, 26766544, 28127548, 28981474). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 99666). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
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:
The TULP1 c.1496-6C>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PS1, PM2, PM3, PP3. Based on this evidence we have classified this variant as Likely Pathogenic.
Comment:
The c.1496-6C>A variant in TULP1 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PS1, PM2, PM3, PP3. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
Comment:
Variant summary: TULP1 c.1496-6C>A alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. One computational tool predict a significant impact on normal splicing by abolishing a 3 prime acceptor site, while three predict the variant no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.8e-05 in 248766 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in TULP1 causing Leber Congenital Amaurosis (8.8e-05 vs 0.0005), allowing no conclusion about variant significance. c.1496-6C>A has been reported in the literature in multiple individuals affected with Retinitis pigmentosa or retinal degeneration. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (pathogenic/likely pathogenic n=6, VUS n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change falls in intron 14 of the TULP1 gene. It does not directly change the encoded amino acid sequence of the TULP1 protein. This variant is present in population databases (rs281865171, gnomAD 0.02%). This variant has been observed in individual(s) with retinitis pigmentosa or cone-rod dystrophy (PMID: 9660588, 26766544, 28127548, 28981474). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 99666). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| The importance of automation in genetic diagnosis: Lessons from analyzing an inherited retinal degeneration cohort with the Mendelian Analysis Toolkit (MATK). | Zampaglione E | Genetics in medicine : official journal of the American College of Medical Genetics | 2022 | PMID: 34906470 |
| Genetic architecture of inherited retinal degeneration in Germany: A large cohort study from a single diagnostic center over a 9-year period. | Weisschuh N | Human mutation | 2020 | PMID: 32531858 |
| Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy. | Jespersgaard C | Scientific reports | 2019 | PMID: 30718709 |
| The Genetic Basis of Pericentral Retinitis Pigmentosa-A Form of Mild Retinitis Pigmentosa. | Comander J | Genes | 2017 | PMID: 28981474 |
| Unravelling the Complexity of Inherited Retinal Dystrophies Molecular Testing: Added Value of Targeted Next-Generation Sequencing. | Bernardis I | BioMed research international | 2016 | PMID: 28127548 |
| Mutation Detection in Patients with Retinal Dystrophies Using Targeted Next Generation Sequencing. | Weisschuh N | PloS one | 2016 | PMID: 26766544 |
| Tubby-like protein-1 mutations in autosomal recessive retinitis pigmentosa. | Gu S | Lancet (London, England) | 1998 | PMID: 9660588 |
| Recessive mutations in the gene encoding the tubby-like protein TULP1 in patients with retinitis pigmentosa. | Hagstrom SA | Nature genetics | 1998 | PMID: 9462750 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TULP1 | - | - | - | - |
Text-mined citations for rs281865171 ...
HelpThese 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 Nov 25, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.