rs1555403942

Variant names:

• chr15-40410819-ACACGCTAATCTCACAGTGCAACCACCAACTAAAAGATACCCTCTCCCCTTGGGGGCCAGTCAGACCTGCTTTCTGTAGCATGCTGCCATGAACCAAATGTGGTTAGGAAGGGGCCATGGATTGCTTTAAAATACTTGAGCCAAAAATAATAAAAATAGGACCAGAACTCTTGCATTGAACAACAGACAGACAACATTTGAAGAGAACTCTAAGAAATGGAAGAGTAGGACTAGCTTCCTTTGCAAAGGGAATGGAAAAAGGAGAGGCATTTTCAGCCTTGTAGCCATTGGGCTTAGAAGAGACTTCTAGGACTTTACCGACACCCTGGTCTGAGAGCGAAGTTTGAAGGGGTTTAATGTGGACAGGAAGAGGCAGTACCAGTGAGCTGCTCTAGGGTACTCTGAGGTTGTAACAAGGCCTGTTGGGGGTTTTCCTTGCAGCTGATCAGTGGTGAGTACATCGGAGCCCTGGCCATGAGTGAGCCCAATGCAGGC-GTTG
• rs1555403942
• NM_002225.5:c.456+22_510delACACGCTAATCTCACAGTGCAACCACCAACTAAAAGATACCCTCTCCCCTTGGGGGCCAGTCAGACCTGCTTTCTGTAGCATGCTGCCATGAACCAAATGTGGTTAGGAAGGGGCCATGGATTGCTTTAAAATACTTGAGCCAAAAATAATAAAAATAGGACCAGAACTCTTGCATTGAACAACAGACAGACAACATTTGAAGAGAACTCTAAGAAATGGAAGAGTAGGACTAGCTTCCTTTGCAAAGGGAATGGAAAAAGGAGAGGCATTTTCAGCCTTGTAGCCATTGGGCTTAGAAGAGACTTCTAGGACTTTACCGACACCCTGGTCTGAGAGCGAAGTTTGAAGGGGTTTAATGTGGACAGGAAGAGGCAGTACCAGTGAGCTGCTCTAGGGTACTCTGAGGTTGTAACAAGGCCTGTTGGGGGTTTTCCTTGCAGCTGATCAGTGGTGAGTACATCGGAGCCCTGGCCATGAGTGAGCCCAATGCAGGCinsGTTG

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_002225.5(IVD):​c.456+22_510delACACGCTAATCTCACAGTGCAACCACCAACTAAAAGATACCCTCTCCCCTTGGGGGCCAGTCAGACCTGCTTTCTGTAGCATGCTGCCATGAACCAAATGTGGTTAGGAAGGGGCCATGGATTGCTTTAAAATACTTGAGCCAAAAATAATAAAAATAGGACCAGAACTCTTGCATTGAACAACAGACAGACAACATTTGAAGAGAACTCTAAGAAATGGAAGAGTAGGACTAGCTTCCTTTGCAAAGGGAATGGAAAAAGGAGAGGCATTTTCAGCCTTGTAGCCATTGGGCTTAGAAGAGACTTCTAGGACTTTACCGACACCCTGGTCTGAGAGCGAAGTTTGAAGGGGTTTAATGTGGACAGGAAGAGGCAGTACCAGTGAGCTGCTCTAGGGTACTCTGAGGTTGTAACAAGGCCTGTTGGGGGTTTTCCTTGCAGCTGATCAGTGGTGAGTACATCGGAGCCCTGGCCATGAGTGAGCCCAATGCAGGCinsGTTG​(p.Leu153_Gly170del) variant causes a splice acceptor, conservative inframe deletion, splice region, synonymous, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. L153L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: IVD NM_002225.5 splice_acceptor, conservative_inframe_deletion, splice_region, synonymous, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.443
• Publications: 0 publications found

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]

IVD Gene-Disease associations (from GenCC):

• isovaleric acidemia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Myriad Women’s Health, G2P, ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 10 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.
• PP5: Variant 15-40410819-ACACGCTAATCTCACAGTGCAACCACCAACTAAAAGATACCCTCTCCCCTTGGGGGCCAGTCAGACCTGCTTTCTGTAGCATGCTGCCATGAACCAAATGTGGTTAGGAAGGGGCCATGGATTGCTTTAAAATACTTGAGCCAAAAATAATAAAAATAGGACCAGAACTCTTGCATTGAACAACAGACAGACAACATTTGAAGAGAACTCTAAGAAATGGAAGAGTAGGACTAGCTTCCTTTGCAAAGGGAATGGAAAAAGGAGAGGCATTTTCAGCCTTGTAGCCATTGGGCTTAGAAGAGACTTCTAGGACTTTACCGACACCCTGGTCTGAGAGCGAAGTTTGAAGGGGTTTAATGTGGACAGGAAGAGGCAGTACCAGTGAGCTGCTCTAGGGTACTCTGAGGTTGTAACAAGGCCTGTTGGGGGTTTTCCTTGCAGCTGATCAGTGGTGAGTACATCGGAGCCCTGGCCATGAGTGAGCCCAATGCAGGC-GTTG is Pathogenic according to our data. Variant chr15-40410819-ACACGCTAATCTCACAGTGCAACCACCAACTAAAAGATACCCTCTCCCCTTGGGGGCCAGTCAGACCTGCTTTCTGTAGCATGCTGCCATGAACCAAATGTGGTTAGGAAGGGGCCATGGATTGCTTTAAAATACTTGAGCCAAAAATAATAAAAATAGGACCAGAACTCTTGCATTGAACAACAGACAGACAACATTTGAAGAGAACTCTAAGAAATGGAAGAGTAGGACTAGCTTCCTTTGCAAAGGGAATGGAAAAAGGAGAGGCATTTTCAGCCTTGTAGCCATTGGGCTTAGAAGAGACTTCTAGGACTTTACCGACACCCTGGTCTGAGAGCGAAGTTTGAAGGGGTTTAATGTGGACAGGAAGAGGCAGTACCAGTGAGCTGCTCTAGGGTACTCTGAGGTTGTAACAAGGCCTGTTGGGGGTTTTCCTTGCAGCTGATCAGTGGTGAGTACATCGGAGCCCTGGCCATGAGTGAGCCCAATGCAGGC-GTTG is described in ClinVar as [Pathogenic]. Clinvar id is 459929.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IVD	NM_002225.5	c.456+22_510delACACGCTAATCTCACAGTGCAACCACCAACTAAAAGATACCCTCTCCCCTTGGGGGCCAGTCAGACCTGCTTTCTGTAGCATGCTGCCATGAACCAAATGTGGTTAGGAAGGGGCCATGGATTGCTTTAAAATACTTGAGCCAAAAATAATAAAAATAGGACCAGAACTCTTGCATTGAACAACAGACAGACAACATTTGAAGAGAACTCTAAGAAATGGAAGAGTAGGACTAGCTTCCTTTGCAAAGGGAATGGAAAAAGGAGAGGCATTTTCAGCCTTGTAGCCATTGGGCTTAGAAGAGACTTCTAGGACTTTACCGACACCCTGGTCTGAGAGCGAAGTTTGAAGGGGTTTAATGTGGACAGGAAGAGGCAGTACCAGTGAGCTGCTCTAGGGTACTCTGAGGTTGTAACAAGGCCTGTTGGGGGTTTTCCTTGCAGCTGATCAGTGGTGAGTACATCGGAGCCCTGGCCATGAGTGAGCCCAATGCAGGCinsGTTG	p.Leu153_Gly170del	splice_acceptor_variant, conservative_inframe_deletion, splice_region_variant, synonymous_variant, intron_variant	Exon 5 of 12	ENST00000487418.8	NP_002216.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IVD	ENST00000487418.8	c.456+22_510delACACGCTAATCTCACAGTGCAACCACCAACTAAAAGATACCCTCTCCCCTTGGGGGCCAGTCAGACCTGCTTTCTGTAGCATGCTGCCATGAACCAAATGTGGTTAGGAAGGGGCCATGGATTGCTTTAAAATACTTGAGCCAAAAATAATAAAAATAGGACCAGAACTCTTGCATTGAACAACAGACAGACAACATTTGAAGAGAACTCTAAGAAATGGAAGAGTAGGACTAGCTTCCTTTGCAAAGGGAATGGAAAAAGGAGAGGCATTTTCAGCCTTGTAGCCATTGGGCTTAGAAGAGACTTCTAGGACTTTACCGACACCCTGGTCTGAGAGCGAAGTTTGAAGGGGTTTAATGTGGACAGGAAGAGGCAGTACCAGTGAGCTGCTCTAGGGTACTCTGAGGTTGTAACAAGGCCTGTTGGGGGTTTTCCTTGCAGCTGATCAGTGGTGAGTACATCGGAGCCCTGGCCATGAGTGAGCCCAATGCAGGCinsGTTG	p.Leu153_Gly170del	splice_acceptor_variant, conservative_inframe_deletion, splice_region_variant, synonymous_variant, intron_variant	Exon 5 of 12	1	NM_002225.5	ENSP00000418397.3

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Isovaleryl-CoA dehydrogenase deficiency Pathogenic:1

Dec 21, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant results in the deletion of part of exon 5 (c.465+22_519delinsGTTG) 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 not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with isovaleric acidemia (PMID: 27904153). ClinVar contains an entry for this variant (Variation ID: 459929). This variant disrupts a region of the IVD protein in which other variant(s) (p.Gly159Ala) have been determined to be pathogenic (PMID: 19099814; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.44

Splicing

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

Other links and lift over

dbSNP: rs1555403942; hg19: chr15-40703018;