VCV001726678.3 - ClinVar

NM_001352514.2(HLCS):c.1942del (p.Arg648fs)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Likely pathogenic
Likely pathogenic (2)

2 out of 2 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001352514.2(HLCS):c.1942del (p.Arg648fs)

Variation ID: 1726678 Accession: VCV001726678.3

Type and length

Deletion, 1 bp

Location

Cytogenetic: 21q22.13 21: 36767236 (GRCh38) [ NCBI UCSC ] 21: 38139537 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Nov 19, 2022	Apr 4, 2026	Jun 18, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001352514.2:c.1942del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001339443.1:p.Arg648fs	frameshift
NM_000411.7:c.1501del
NM_000411.8:c.1501del	NP_000402.3:p.Arg501fs	frameshift
NM_001242784.3:c.1501del	NP_001229713.1:p.Arg501fs	frameshift
NM_001242785.2:c.1501del	NP_001229714.1:p.Arg501fs	frameshift
NM_001352515.2:c.1501del	NP_001339444.1:p.Arg501fs	frameshift
NM_001352516.2:c.1501del	NP_001339445.1:p.Arg501fs	frameshift
NM_001352517.1:c.1501del	NP_001339446.1:p.Arg501fs	frameshift
NM_001352518.2:c.1501del	NP_001339447.1:p.Arg501fs	frameshift
NR_148020.2:n.1801del		non-coding transcript variant
NR_148021.1:n.1958del		non-coding transcript variant
NC_000021.9:g.36767238del
NC_000021.8:g.38139539del
NG_016193.2:g.228159del

... more HGVS ... less HGVS

Protein change

R501fs, R648fs

Other names

Canonical SPDI

NC_000021.9:36767235:GGG:GG

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA2388161238 dbSNP: rs2090070597 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
HLCS		Gene associated with autosomal recessive phenotype	No evidence available	GRCh38 GRCh37	1110	1210

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Holocarboxylase synthetase deficiency	Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jun 18, 2024	RCV002310362.3

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Dec 30, 2021) C Contributing to aggregate classification	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021))	Holocarboxylase synthetase deficiency	Myriad Genetics, Inc. Accession: SCV002602346.2 First in ClinVar: Nov 19, 2022 Last updated: Dec 24, 2022	Comment: show NM_000411.6(HLCS):c.1501delC(R501Gfs*14) is expected to be pathogenic in the context of holocarboxylase synthetase deficiency. This variant is predicted to lead to an abnormal or absent protein product due to the creation of a premature termination codon in HLCS, a gene where loss-of-function variants are known to be pathogenic. Please note: this variant was assessed in the context of healthy population screening. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Likely pathogenic (Jun 18, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Natera Variant Classification Schema (03/2026))	Holocarboxylase synthetase deficiency	Natera, Inc. Accession: SCV007530314.1 First in ClinVar: Apr 04, 2026 Last updated: Apr 04, 2026	Comment: show The c.1501del variant in HLCS is a frameshift variant predicted to shift the reading frame beginning at codon 501 and leads to a stop codon 14 codons downstream. This variant is expected to result in nonsense mediated decay, truncation, or a dysfunctional protein product. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). Given the available evidence, this variant is classified as Likely Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

NM_000411.6(HLCS):c.1501delC(R501Gfs*14) is expected to be pathogenic in the context of holocarboxylase synthetase deficiency. This variant is predicted to lead to an abnormal or absent protein product due to the creation of a premature termination codon in HLCS, a gene where loss-of-function variants are known to be pathogenic. Please note: this variant was assessed in the context of healthy population screening.

Comment:

The c.1501del variant in HLCS is a frameshift variant predicted to shift the reading frame beginning at codon 501 and leads to a stop codon 14 codons downstream. This variant is expected to result in nonsense mediated decay, truncation, or a dysfunctional protein product. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). Given the available evidence, this variant is classified as Likely Pathogenic.

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs2090070597 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Apr 13, 2026