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NM_002225.5(IVD):c.464GTG[3] (p.Gly156dup) AND Isovaleryl-CoA dehydrogenase deficiency

Germline classification:
Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:
Dec 30, 2023
Review status:
criteria provided, conflicting classifications
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:
RCV001040480.8

Allele description [Variation Report for NM_002225.5(IVD):c.464GTG[3] (p.Gly156dup)]

NM_002225.5(IVD):c.464GTG[3] (p.Gly156dup)

Gene:
IVD:isovaleryl-CoA dehydrogenase [Gene - OMIM - HGNC]
Variant type:
Microsatellite
Cytogenetic location:
15q15.1
Genomic location:
Preferred name:
NM_002225.5(IVD):c.464GTG[3] (p.Gly156dup)
HGVS:
  • NC_000015.10:g.40411267GTG[3]
  • NG_011986.2:g.10783GTG[3]
  • NM_001159508.3:c.374GTG[3]
  • NM_001354597.3:c.416GTG[3]
  • NM_001354598.3:c.464GTG[3]
  • NM_001354599.3:c.551GTG[3]
  • NM_001354600.3:c.551GTG[3]
  • NM_001354601.3:c.464GTG[3]
  • NM_002225.5:c.464GTG[3]MANE SELECT
  • NP_001152980.2:p.Gly126dup
  • NP_001341526.1:p.Gly140dup
  • NP_001341527.2:p.Gly156dup
  • NP_001341528.2:p.Gly185dup
  • NP_001341529.2:p.Gly185dup
  • NP_001341530.2:p.Gly156dup
  • NP_002216.3:p.Gly156dup
  • NC_000015.9:g.40703465_40703466insGTG
  • NC_000015.9:g.40703466GTG[3]
  • NM_002225.3:c.476_478dup
  • NM_002225.3:c.476_478dupGTG
  • NM_002225.5:c.467_469dupMANE SELECT
  • NR_148925.2:n.876GTG[3]
  • p.G159_E160insG
Links:
dbSNP: rs796051982
NCBI 1000 Genomes Browser:
rs796051982
Molecular consequence:
  • NM_001159508.3:c.374GTG[3] - inframe_insertion - [Sequence Ontology: SO:0001821]
  • NM_001354597.3:c.416GTG[3] - inframe_insertion - [Sequence Ontology: SO:0001821]
  • NM_001354598.3:c.464GTG[3] - inframe_insertion - [Sequence Ontology: SO:0001821]
  • NM_001354599.3:c.551GTG[3] - inframe_insertion - [Sequence Ontology: SO:0001821]
  • NM_001354600.3:c.551GTG[3] - inframe_insertion - [Sequence Ontology: SO:0001821]
  • NM_001354601.3:c.464GTG[3] - inframe_insertion - [Sequence Ontology: SO:0001821]
  • NM_002225.5:c.464GTG[3] - inframe_insertion - [Sequence Ontology: SO:0001821]
  • NR_148925.2:n.876GTG[3] - 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
SCV001204056Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Uncertain significance
(Dec 30, 2023)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV002060118Myriad Genetics, Inc.
criteria provided, single submitter

(Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021))
Uncertain significance
(Nov 3, 2021)
unknownclinical testing

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

Citation Link,

SCV004198027Baylor Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Nov 22, 2023)
unknownclinical testing

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

Summary from all submissions

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

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Molecular analysis using targeted next generation DNA sequencing and clinical spectrum of Mexican patients with isovaleric acidemia.

Ibarra-González I, Fernández-Lainez C, Guillén-López S, López-Mejía L, Belmont-Matínez L, Sokolsky TD, Amin VR, Kitchener RL, Vela-Amieva M, Naylor EW, Bhattacharjee A.

Clin Chim Acta. 2020 Feb;501:216-221. doi: 10.1016/j.cca.2019.10.041. Epub 2019 Nov 9.

PubMed [citation]
PMID:
31707166
See all PubMed Citations (3)

Details of each submission

From Invitae, SCV001204056.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This variant, c.476_478dup, results in the insertion of 1 amino acid(s) of the IVD protein (p.Gly159dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs796051982, gnomAD 0.009%). This variant has been observed in individual(s) with isovaleric acidemia (PMID: 31707166). This variant is also known as c.472_473insGTG (p.Ser158_Gly159insGly). ClinVar contains an entry for this variant (Variation ID: 203791). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

From Myriad Genetics, Inc., SCV002060118.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

NM_002225.3(IVD):c.476_478dupGTG(G159dup) is an in-frame duplication classified as a variant of uncertain significance in the context of isovaleric acidemia. G159dup has been observed in cases with relevant disease (PMID: 31707166). Functional assessments of this variant are not available in the literature. G159dup has been observed in population frequency databases (gnomAD: AMR 0.01%). In summary, there is insufficient evidence to classify NM_002225.3(IVD):c.476_478dupGTG(G159dup) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.

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

From Baylor Genetics, SCV004198027.2

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

Last Updated: Jun 17, 2024