NM_001352514.2(HLCS):c.1850T>C (p.Leu617Ser) AND Holocarboxylase synthetase deficiency

Germline classification:: Conflicting classifications of pathogenicity (2 submissions)
Last evaluated:: Jul 18, 2022
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:: RCV000669490.4

Allele description [Variation Report for NM_001352514.2(HLCS):c.1850T>C (p.Leu617Ser)]

NM_001352514.2(HLCS):c.1850T>C (p.Leu617Ser)

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.1850T>C (p.Leu617Ser)

HGVS:

NC_000021.9:g.36896902A>G
NG_016193.2:g.98493T>C
NM_000411.8:c.1409T>C
NM_001242784.3:c.1409T>C
NM_001242785.2:c.1409T>C
NM_001352514.2:c.1850T>CMANE SELECT
NM_001352515.2:c.1409T>C
NM_001352516.2:c.1409T>C
NM_001352517.1:c.1409T>C
NM_001352518.2:c.1409T>C
NP_000402.3:p.Leu470Ser
NP_001229713.1:p.Leu470Ser
NP_001229714.1:p.Leu470Ser
NP_001339443.1:p.Leu617Ser
NP_001339444.1:p.Leu470Ser
NP_001339445.1:p.Leu470Ser
NP_001339446.1:p.Leu470Ser
NP_001339447.1:p.Leu470Ser
NC_000021.8:g.38269202A>G
NM_000411.6:c.1409T>C
NR_148020.2:n.1709T>C
NR_148021.1:n.1866T>C

Protein change:

L470S

Links:

dbSNP: rs1261821166

NCBI 1000 Genomes Browser:

rs1261821166

Molecular consequence:

NM_000411.8:c.1409T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001242784.3:c.1409T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001242785.2:c.1409T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001352514.2:c.1850T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001352515.2:c.1409T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001352516.2:c.1409T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001352517.1:c.1409T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001352518.2:c.1409T>C - missense variant - [Sequence Ontology: SO:0001583]
NR_148020.2:n.1709T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_148021.1:n.1866T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000794247	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Sep 20, 2017)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV002570590	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Jul 18, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000794247

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))

Uncertain significance
(Sep 20, 2017)

unknown

clinical testing

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

Citation Link,

SCV002570590

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Jul 18, 2022)

germline

clinical testing

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

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

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

Details of each submission

From Counsyl, SCV000794247.1

#	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	unknown	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, SCV002570590.1

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

Description

Variant summary: HLCS c.1409T>C (p.Leu470Ser) results in a non-conservative amino acid change located in the biotinyl protein ligase (BPL) and lipoyl protein ligase (LPL), catalytic domain (IPR004143) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251462 control chromosomes (gnomAD). c.1409T>C has been reported in the literature in at least one compound heterozygous individual affected with Holocarboxylase Synthetase Deficiency (e.g. Yang_2001). In an experimental study the variant protein was found to have approximately 4% enzyme activity compared to the wild-type, suggesting the variant impairs protein function (Yang_2001). One clinical diagnostic laboratory has submitted an assessment for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely 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: Jan 19, 2025

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