Submissions for variant NM_002225.5(IVD):c.550+1G>A

gnomAD frequency: 0.00007  dbSNP: rs377147994

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413513	SCV000490570	pathogenic	not provided	2023-10-24	criteria provided, single submitter	clinical testing	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)
Baylor Genetics	RCV000984189	SCV001163384	pathogenic	Isovaleryl-CoA dehydrogenase deficiency		criteria provided, single submitter	clinical testing
Invitae	RCV000984189	SCV001222259	pathogenic	Isovaleryl-CoA dehydrogenase deficiency	2024-01-13	criteria provided, single submitter	clinical testing	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.
New York Genome Center	RCV000984189	SCV001480433	likely pathogenic	Isovaleryl-CoA dehydrogenase deficiency	2020-05-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000984189	SCV002598727	likely pathogenic	Isovaleryl-CoA dehydrogenase deficiency	2022-09-29	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV002523909	SCV003644991	uncertain significance	Inborn genetic diseases	2021-07-14	criteria provided, single submitter	clinical testing	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.
PreventionGenetics, part of Exact Sciences	RCV003401395	SCV004120568	likely pathogenic	IVD-related condition	2022-11-29	criteria provided, single submitter	clinical testing	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.
Counsyl	RCV000984189	SCV001132236	likely pathogenic	Isovaleryl-CoA dehydrogenase deficiency	2014-01-02	no assertion criteria provided	clinical testing