rs786204427

Variant names:

• chr15-40411257-CA-GG
• rs786204427
• NM_002225.5:c.457-3_457-2delCAinsGG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_002225.5(IVD):​c.457-3_457-2delCAinsGG variant causes a splice acceptor, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IVD NM_002225.5 splice_acceptor, splice_region, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 8.90

Genes affected

IVD (HGNC:6186): (isovaleryl-CoA dehydrogenase) Isovaleryl-CoA dehydrogenase (IVD) is a mitochondrial matrix enzyme that catalyzes the third step in leucine catabolism. The genetic deficiency of IVD results in an accumulation of isovaleric acid, which is toxic to the central nervous system and leads to isovaleric acidemia. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-40411257-CA-GG is Pathogenic according to our data. Variant chr15-40411257-CA-GG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IVD	NM_002225.5	c.457-3_457-2delCAinsGG		splice_acceptor_variant, splice_region_variant, intron_variant	Intron 4 of 11	ENST00000487418.8	NP_002216.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IVD	ENST00000487418.8	c.457-3_457-2delCAinsGG		splice_acceptor_variant, splice_region_variant, intron_variant	Intron 4 of 11	1	NM_002225.5	ENSP00000418397.3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Isovaleryl-CoA dehydrogenase deficiency Pathogenic:2

Mar 18, 2014

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a splice site in intron 4 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). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. Disruption of this splice site has been observed in individuals with isovaleric acidemia (PMID: 17576084, 22004070; internal data). This variant is also known as c.457–3_2CA>GG. ClinVar contains an entry for this variant (Variation ID: 188724). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs786204427; hg19: chr15-40703456;