NM_001352514.2(HLCS):c.1439T>A (p.Val480Glu) AND Holocarboxylase synthetase deficiency

Clinical significance:Likely pathogenic (Last evaluated: Mar 22, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:

Allele description [Variation Report for NM_001352514.2(HLCS):c.1439T>A (p.Val480Glu)]

NM_001352514.2(HLCS):c.1439T>A (p.Val480Glu)

HLCS:holocarboxylase synthetase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_001352514.2(HLCS):c.1439T>A (p.Val480Glu)
  • NC_000021.9:g.36930432A>T
  • NG_016193.2:g.64963T>A
  • NM_000411.8:c.998T>A
  • NM_001242784.3:c.998T>A
  • NM_001242785.2:c.998T>A
  • NM_001352514.2:c.1439T>AMANE SELECT
  • NM_001352515.2:c.998T>A
  • NM_001352516.2:c.998T>A
  • NM_001352517.1:c.998T>A
  • NM_001352518.2:c.998T>A
  • NP_000402.3:p.Val333Glu
  • NP_001229713.1:p.Val333Glu
  • NP_001229714.1:p.Val333Glu
  • NP_001339443.1:p.Val480Glu
  • NP_001339444.1:p.Val333Glu
  • NP_001339445.1:p.Val333Glu
  • NP_001339446.1:p.Val333Glu
  • NP_001339447.1:p.Val333Glu
  • NC_000021.8:g.38302732A>T
  • NR_148020.2:n.1298T>A
  • NR_148021.1:n.1455T>A
Protein change:
Molecular consequence:
  • NM_000411.8:c.998T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001242784.3:c.998T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001242785.2:c.998T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001352514.2:c.1439T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001352515.2:c.998T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001352516.2:c.998T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001352517.1:c.998T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001352518.2:c.998T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NR_148020.2:n.1298T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_148021.1:n.1455T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]


Holocarboxylase synthetase deficiency
MONDO: MONDO:0009666; MedGen: C0268581; Orphanet: 79242; OMIM: 253270

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV001575464Invitaecriteria provided, single submitter
Likely pathogenic
(Mar 22, 2020)
germlineclinical testing

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

Summary from all submissions

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



Structure of human holocarboxylase synthetase gene and mutation spectrum of holocarboxylase synthetase deficiency.

Yang X, Aoki Y, Li X, Sakamoto O, Hiratsuka M, Kure S, Taheri S, Christensen E, Inui K, Kubota M, Ohira M, Ohki M, Kudoh J, Kawasaki K, Shibuya K, Shintani A, Asakawa S, Minoshima S, Shimizu N, Narisawa K, Matsubara Y, Suzuki Y.

Hum Genet. 2001 Nov;109(5):526-34. Epub 2001 Oct 5.

PubMed [citation]

Identification and characterization of mutations in patients with holocarboxylase synthetase deficiency.

Aoki Y, Li X, Sakamoto O, Hiratsuka M, Akaishi H, Xu L, Briones P, Suormala T, Baumgartner ER, Suzuki Y, Narisawa K.

Hum Genet. 1999 Feb;104(2):143-8.

PubMed [citation]
See all PubMed Citations (4)

Details of each submission

From Invitae, SCV001575464.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)


This sequence change replaces valine with glutamic acid at codon 433 of the HLCS protein (p.Val333Glu). The valine residue is moderately conserved and there is a moderate physicochemical difference between valine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with holocarboxylase synthetase deficiency (PMID: 10190325, 11735028, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant has been reported to affect HLCS protein function (PMID: 10190325, 10590022). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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

Last Updated: Oct 7, 2021

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