rs767533946

Positions:

• chr21-36765158-C-CA

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001352514.2(HLCS):​c.1974_1975insT​(p.Val659CysfsTer65) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000217 in 1,614,112 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: HLCS NM_001352514.2 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:1
• Conservation: PhyloP100: -1.40

Genes affected

HLCS (HGNC:4976): (holocarboxylase synthetase) This gene encodes an enzyme that catalyzes the binding of biotin to carboxylases and histones. The protein plays an important role in gluconeogenesis, fatty acid synthesis and branched chain amino acid catabolism. Defects in this gene are the cause of holocarboxylase synthetase deficiency. Multiple alternatively spliced variants, encoding the same protein, have been identified.[provided by RefSeq, Jun 2011]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 21-36765158-C-CA is Pathogenic according to our data. Variant chr21-36765158-C-CA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 370850.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=5, Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLCS	NM_001352514.2	c.1974_1975insT	p.Val659CysfsTer65	frameshift_variant	8/11	ENST00000674895.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLCS	ENST00000674895.3	c.1974_1975insT	p.Val659CysfsTer65	frameshift_variant	8/11		NM_001352514.2	P4

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000477 AC: 12 AN: 251434 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135902

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000967

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000231 AC: 337 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.000237 AC XY: 172 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000296

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152230 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74372

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.0000529

EpiCase AF: 0.000109

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Holocarboxylase synthetase deficiency Pathogenic:4 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 12, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 13, 2018	The HLCS c.1533dupT (p.Val512CysfsTer65) variant is a frameshift variant that is predicted to result in premature termination of the protein. The p.Val512CysfsTer65 variant has been reported in two studies, in which it is found in two individuals with holocarboxylase synthetase deficiency, including in a compound heterozygous state in one individual and in a heterozygous state in a second individual who also carries two additional missense variants of unknown phase (DaRe et al. 2013; Reid et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.000095 in the European (non-Finnish) population of the Genome Aggregation Database. Due to the potential impact of frameshift variants and evidence from the literature, the p.Val512CysfsTer65 variant is classified as a variant of unknown significance but suspicious for holocarboxylase synthetase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jul 22, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	This sequence change creates a premature translational stop signal (p.Val512Cysfs*65) in the HLCS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HLCS are known to be pathogenic (PMID: 16134170). This variant is present in population databases (rs767533946, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with a mitochondrial disorder (PMID: 24215330). ClinVar contains an entry for this variant (Variation ID: 370850). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Mar 01, 2019	This frameshifting variant in exon 9 of 12 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function. This variant has been previously reported as a heterozygous change in two patients with suspected metabolic disease (PMID 24215330, 27604308) and classified in the ClinVar database as Likely Pathogenic by a clinical laboratory (Variation ID: 370850). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.001% (15/277210) and thus is presumed to be rare. Based on the available evidence, the c.1533dup, p.Val512CysfsTer65 variant is classified as Pathogenic. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 13, 2021

The c.1533dupT (p.V512Cfs*65) alteration, located in exon 9 (coding exon 6) of the HLCS gene, consists of a duplication of T at position 1533, causing a translational frameshift with a predicted alternate stop codon after 65 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration has been reported in the heterozygous state along with two other HLCS variants in a patient diagnosed with holocarboxylase synthetase deficiency; however, parental testing to determine the phase of these variants was not available (Reid, 2016). Based on the available evidence, this alteration is classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 02, 2023

Previously reported in a patient with a neurometabolic phenotype who was also found to have a second variant in the HLCS gene (Reid et al., 2016); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24215330, 27604308, 33870574) -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs767533946; hg19: chr21-38137459;