ClinVar Genomic variation as it relates to human health
NM_002225.5(IVD):c.550+1G>A
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.
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(3); Likely pathogenic(3); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002225.5(IVD):c.550+1G>A
Variation ID: 372389 Accession: VCV000372389.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q15.1 15: 40411354 (GRCh38) [ NCBI UCSC ] 15: 40703553 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Jan 9, 2017 Feb 14, 2024 Jan 13, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002225.5:c.550+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001159508.3:c.460+1G>A splice donor NM_001354597.3:c.502+1G>A splice donor NM_001354598.3:c.550+1G>A splice donor NM_001354599.3:c.637+1G>A splice donor NM_001354600.3:c.637+1G>A splice donor NM_001354601.3:c.550+1G>A splice donor NC_000015.10:g.40411354G>A NC_000015.9:g.40703553G>A NG_011986.2:g.10870G>A - Protein change
- Other names
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- Canonical SPDI
- NC_000015.10:40411353:G:A
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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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0.00020 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
Trans-Omics for Precision Medicine (TOPMed) 0.00020
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00007
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
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 | ||
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HI score
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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. |
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IVD | - | - |
GRCh38 GRCh37 |
736 | 745 |
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. |
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Pathogenic (1) |
criteria provided, single submitter
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Oct 24, 2023 | RCV000413513.2 | |
Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jan 13, 2024 | RCV000984189.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 14, 2021 | RCV002523909.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Nov 29, 2022 | RCV003401395.4 |
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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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Isovaleryl-CoA dehydrogenase deficiency
Affected status: unknown
Allele origin:
germline
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Baylor Genetics
Accession: SCV001163384.1
First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020 |
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Likely pathogenic
(May 26, 2020)
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criteria provided, single submitter
Method: clinical testing
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Isovaleryl-CoA dehydrogenase deficiency
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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New York Genome Center
Study: CSER-NYCKidSeq
Accession: SCV001480433.1 First in ClinVar: Feb 20, 2021 Last updated: Feb 20, 2021 |
Clinical Features:
Intellectual disability (present) , Autism (present)
Secondary finding: no
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Likely pathogenic
(Sep 29, 2022)
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criteria provided, single submitter
Method: clinical testing
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Isovaleryl-CoA dehydrogenase deficiency
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002598727.1
First in ClinVar: Nov 05, 2022 Last updated: Nov 05, 2022 |
Comment:
Variant summary: IVD c.550+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to … (more)
Variant summary: IVD c.550+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 251444 control chromosomes (gnomAD). To our knowledge c.550+1G>A has not been reported in the literature in individuals affected with Isovaleryl-CoA Dehydrogenase Deficiency and no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Uncertain significance
(Jul 14, 2021)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003644991.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The c.559+1G>A intronic alteration consists of a G to A substitution one nucleotide after exon 5 of the IVD gene. Alterations that disrupt the canonical … (more)
The c.559+1G>A intronic alteration consists of a G to A substitution one nucleotide after exon 5 of the IVD gene. Alterations that disrupt the canonical splice donor site are typically deleterious in nature (Richards, 2015). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Nov 29, 2022)
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criteria provided, single submitter
Method: clinical testing
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IVD-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004120568.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The IVD c.559+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. To our knowledge this variant has not been … (more)
The IVD c.559+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. To our knowledge this variant has not been reported in the literature. This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-40703553-G-A). Variants that disrupt the consensus splice donor site in IVD are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
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Pathogenic
(Oct 24, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000490570.3
First in ClinVar: Jan 09, 2017 Last updated: Nov 25, 2023 |
Comment:
Observed in patient with inborn error of metabolism in published literature; however, no further clinical information was provided (PMID: 32778825); Canonical splice site variant predicted … (more)
Observed in patient with inborn error of metabolism in published literature; however, no further clinical information was provided (PMID: 32778825); Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.550+1 G>A; This variant is associated with the following publications: (PMID: 16602101, 16199547, 32778825) (less)
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Pathogenic
(Jan 13, 2024)
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criteria provided, single submitter
Method: clinical testing
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Isovaleryl-CoA dehydrogenase deficiency
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001222259.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects a donor splice site in intron 5 of the IVD gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more)
This sequence change affects a donor splice site in intron 5 of the IVD gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in IVD are known to be pathogenic (PMID: 16602101). This variant is present in population databases (rs377147994, gnomAD 0.007%). Disruption of this splice site has been observed in individual(s) with clinical features of isovaleric acidemia (Invitae). 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: 372389). 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
(Jan 02, 2014)
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no assertion criteria provided
Method: clinical testing
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Isovaleryl-CoA dehydrogenase deficiency
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV001132236.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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The role of exome sequencing in newborn screening for inborn errors of metabolism. | Adhikari AN | Nature medicine | 2020 | PMID: 32778825 |
Isovaleric acidemia: new aspects of genetic and phenotypic heterogeneity. | Vockley J | American journal of medical genetics. Part C, Seminars in medical genetics | 2006 | PMID: 16602101 |
Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
Text-mined citations for rs377147994 ...
HelpRecord last updated Mar 11, 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.