NM_001352514.2(HLCS):c.1960+5G>A AND Holocarboxylase synthetase deficiency

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Oct 20, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
5 submissions [Details]
Record status:
current
Accession:
RCV000001989.9

Allele description [Variation Report for NM_001352514.2(HLCS):c.1960+5G>A]

NM_001352514.2(HLCS):c.1960+5G>A

Gene:
HLCS:holocarboxylase synthetase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
21q22.13
Genomic location:
Preferred name:
NM_001352514.2(HLCS):c.1960+5G>A
HGVS:
  • NC_000021.9:g.36767213C>T
  • NG_016193.1:g.228023G>A
  • NG_016193.2:g.228182G>A
  • NM_000411.8:c.1519+5G>A
  • NM_001242784.3:c.1519+5G>A
  • NM_001242785.2:c.1519+5G>A
  • NM_001352514.2:c.1960+5G>AMANE SELECT
  • NM_001352515.2:c.1519+5G>A
  • NM_001352516.2:c.1519+5G>A
  • NM_001352517.1:c.1519+5G>A
  • NM_001352518.1:c.1519+5G>A
  • NC_000021.8:g.38139514C>T
  • NM_000411.6:c.1519+5G>A
Note:
NCBI staff compared the intron-exon definition in AB063285.1 and the primers used to define the intron/exon boundaries in the paper by Yang et al., 2001 (PubMed 11735028) to define the location of this substitution.
Nucleotide change:
IVS10DS, G-A, +5
Links:
OMIM: 609018.0007; dbSNP: rs753887925
NCBI 1000 Genomes Browser:
rs753887925
Molecular consequence:
  • NM_000411.8:c.1519+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001242784.3:c.1519+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001242785.2:c.1519+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001352514.2:c.1960+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001352515.2:c.1519+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001352516.2:c.1519+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001352517.1:c.1519+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001352518.1:c.1519+5G>A - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:
Holocarboxylase synthetase deficiency
Synonyms:
MULTIPLE CARBOXYLASE DEFICIENCY, EARLY ONSET
Identifiers:
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)
OriginMethodCitations
SCV000022147OMIMno assertion criteria providedPathogenic
(Nov 1, 2001)
germlineliterature only

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

SCV000795403Counsylcriteria provided, single submitter
Likely pathogenic
(Nov 8, 2017)
unknownclinical testing

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

Citation Link,

SCV000919518Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Aug 10, 2018)
germlineclinical testing

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

Citation Link,

SCV000949761Invitaecriteria provided, single submitter
Pathogenic
(Oct 20, 2020)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV001456938Natera, Inc.no assertion criteria providedPathogenic
(Sep 16, 2020)
germlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

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]
PMID:
11735028

Holocarboxylase synthetase deficiency pre and post newborn screening.

Donti TR, Blackburn PR, Atwal PS.

Mol Genet Metab Rep. 2016 Jun;7:40-4. doi: 10.1016/j.ymgmr.2016.03.007.

PubMed [citation]
PMID:
27114915
PMCID:
PMC4832086
See all PubMed Citations (6)

Details of each submission

From OMIM, SCV000022147.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

In a large survey of HLCS mutations in patients with biotin-responsive multiple carboxylase deficiency (253270), Yang et al. (2001) identified an IVS10+5G-A mutation in 6 patients: 2 patients from the Faroe Islands and a Spanish and a Danish patient were homozygous for the mutation; and a French and a German patient were heterozygous. The haplotype of the HLCS gene in all 6 patients was identical, suggesting a founder mutation.

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

From Counsyl, SCV000795403.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000919518.1

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

Description

Variant summary: HLCS c.1519+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant weakens a 5' donor site, while one predicts the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, with skipping of exon 10 in vitro and in a homozygous patient cell line (Sakamoto_2000). In addition, assays for HCS activity in these patient fibroblasts revealed levels at 4% of control activity. The variant allele was found at a frequency of 6.9e-05 in 277238 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in HLCS causing Holocarboxylase Synthetase Deficiency (6.9e-05 vs 0.0028), allowing no conclusion about variant significance. The variant, c.1519+5G>A, has been reported in the literature in multiple individuals affected with Holocarboxylase Synthetase Deficiency and is likely a Scandinavian founder mutation (Sakamoto_2000, Yang_2001). These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as 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

From Invitae, SCV000949761.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This sequence change falls in intron 8 of the HLCS gene. It does not directly change the encoded amino acid sequence of the HLCS protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs753887925, ExAC 0.02%). This variant has been observed to be homozygous or in combination with another HLCS variant in several individuals affected with holocarboxylase synthetase defficiency (PMID: 10653324, 11735028, 27114915). This variant is also known as IVS10+5G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 1912). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing and is expected to lead to the loss of protein expression (PMID: 10653324). 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., SCV001456938.1

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

Last Updated: Aug 19, 2021

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