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

Germline classification:
Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:
Mar 25, 2024
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:
RCV000169289.12

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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000220605Counsyl
criteria provided, single submitter

(Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))
Likely pathogenic
(Aug 19, 2014)
unknownliterature only

PubMed (4)
[See all records that cite these PMIDs]

Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015),

Citation Link,

SCV000893369Fulgent Genetics, Fulgent Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Sep 29, 2021)
unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001163380Baylor Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Mar 25, 2024)
unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001578737Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Sep 13, 2020)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV002094382Natera, Inc.
no assertion criteria provided
Pathogenic
(Mar 17, 2017)
germlineclinical testing

SCV004100218Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Pathogenic
(Sep 27, 2023)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical 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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (4)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Fulgent Genetics, Fulgent Genetics, SCV000893369.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Baylor Genetics, SCV001163380.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001578737.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Natera, Inc., SCV002094382.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 15, 2024