NM_002225.5(IVD):c.149G>C (p.Arg50Pro) AND Isovaleryl-CoA dehydrogenase deficiency

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: Sep 27, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000169289.11

Allele description [Variation Report for NM_002225.5(IVD):c.149G>C (p.Arg50Pro)]

NM_002225.5(IVD):c.149G>C (p.Arg50Pro)

Gene:

IVD:isovaleryl-CoA dehydrogenase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q15.1

Genomic location:

Preferred name:

NM_002225.5(IVD):c.149G>C (p.Arg50Pro)

HGVS:

NC_000015.10:g.40407640G>C
NG_011986.2:g.7156G>C
NM_001159508.3:c.145-299G>C
NM_001354597.3:c.101G>C
NM_001354598.3:c.149G>C
NM_001354599.3:c.149G>C
NM_001354600.3:c.149G>C
NM_001354601.3:c.149G>C
NM_002225.5:c.149G>CMANE SELECT
NP_001341526.1:p.Arg34Pro
NP_001341527.2:p.Arg50Pro
NP_001341528.2:p.Arg50Pro
NP_001341529.2:p.Arg50Pro
NP_001341530.2:p.Arg50Pro
NP_002216.3:p.Arg50Pro
NC_000015.9:g.40699841G>C
NM_002225.3:c.158G>C
NR_148925.2:n.561G>C

Protein change:

R34P

Links:

dbSNP: rs2229311

NCBI 1000 Genomes Browser:

rs2229311

Molecular consequence:

NM_001159508.3:c.145-299G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001354597.3:c.101G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354598.3:c.149G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354599.3:c.149G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354600.3:c.149G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354601.3:c.149G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_002225.5:c.149G>C - missense variant - [Sequence Ontology: SO:0001583]
NR_148925.2:n.561G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Isovaleryl-CoA dehydrogenase deficiency (IVA)
Synonyms:: Isovaleric acid CoA dehydrogenase deficiency; Isovaleric acidemia; Isovaleryl CoA carboxylase deficiency; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009475; MedGen: C0268575; Orphanet: 33; OMIM: 243500

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000220605	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Aug 19, 2014)	unknown	literature only	PubMed (4) [See all records that cite these PMIDs] 16825284, 15486829, 9665741, 10677295 Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015), Citation Link,
SCV000893369	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 29, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001163380	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001578737	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 13, 2020)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 27904153, 26018748, 9665741, 110677295, 28492532
SCV002094382	Natera, Inc.	no assertion criteria provided	Pathogenic (Mar 17, 2017)	germline	clinical testing
SCV004100218	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Sep 27, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9665741, 27904153, 15486829 Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only

Citations

PubMed

An increased specificity score matrix for the prediction of SF2/ASF-specific exonic splicing enhancers.

Smith PJ, Zhang C, Wang J, Chew SL, Zhang MQ, Krainer AR.

Hum Mol Genet. 2006 Aug 15;15(16):2490-508. Epub 2006 Jul 6.

PubMed [citation]

PMID:: 16825284

Exon skipping in IVD RNA processing in isovaleric acidemia caused by point mutations in the coding region of the IVD gene.

Vockley J, Rogan PK, Anderson BD, Willard J, Seelan RS, Smith DI, Liu W.

Am J Hum Genet. 2000 Feb;66(2):356-67.

PubMed [citation]

PMID:: 10677295
PMCID:: PMC1288088

See all PubMed Citations (9)

PMC

Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL.

Genetics in medicine : official journal of the American College of Medical Genetics. 2015 Mar 5; 17(5): 405-424

PMC [article]

PMCID:: PMC4544753
PMID:: 25741868
DOI:: 10.1038/gim.2015.30

Details of each submission

From Counsyl, SCV000220605.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (4)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV000893369.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV001163380.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV001578737.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces arginine with proline at codon 53 of the IVD protein (p.Arg53Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is present in population databases (rs2229311, ExAC 0.02%). This variant has been observed in individual(s) with isovaleric acidemia (PMID: 27904153, 26018748, 9665741). This variant is also known as p.Arg21Pro in the literature. ClinVar contains an entry for this variant (Variation ID: 188922). This variant has been reported to affect IVD protein function (PMID: 9665741). This variant disrupts the p.Arg53 amino acid residue in IVD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 110677295). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV002094382.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004100218.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: IVD c.149G>C (p.Arg50Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251478 control chromosomes (gnomAD). c.149G>C has been reported in the literature in individuals affected with Isovaleryl-CoA Dehydrogenase Deficiency (examples: Mohsen_1998, Ensenauer_2004, and Couce_2017). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Mohsen_1998). The following publications have been ascertained in the context of this evaluation (PMID: 27904153, 15486829, 9665741). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 15, 2024

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