rs771944310

Positions:

• chr21-36936662-AC-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001352514.2(HLCS):​c.1223delG​(p.Gly408fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,614,076 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: HLCS NM_001352514.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: -0.159

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]

HLCS (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 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 21-36936662-AC-A is Pathogenic according to our data. Variant chr21-36936662-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 203777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLCS	NM_001352514.2	c.1223delG	p.Gly408fs	frameshift_variant	4/11	ENST00000674895.3	NP_001339443.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLCS	ENST00000674895.3	c.1223delG	p.Gly408fs	frameshift_variant	4/11		NM_001352514.2	ENSP00000502087.2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251148 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135764

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461886 Hom.: 0 Cov.: 34 AF XY: 0.0000124 AC XY: 9 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74350

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000770

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Holocarboxylase synthetase deficiency Pathogenic:8

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 29, 2023	This sequence change creates a premature translational stop signal (p.Gly261Valfs*20) 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 (rs771944310, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with holocarboxylase synthetase deficiency (PMID: 7842009, 9870216, 11735028). This variant is also known as delG1067, c.780delG. ClinVar contains an entry for this variant (Variation ID: 203777). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 21, 2017	Variant summary: The HLCS c.782delG (p.Gly261ValfsX20) variant results in a premature termination codon, predicted to cause a truncated or absent HLCS protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 5/276850 control chromosomes at a frequency of 0.0000181, which does not exceed the estimated maximal expected allele frequency of a pathogenic HLCS variant (0.0027839). The variant of interest has been reported in multiple compound heterozygote individuals and has been indicated to be a common mutation observed in Japanese (Yang_2001). In addition, multiple clinical diagnostic laboratories classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	curation	SingHealth Duke-NUS Institute of Precision Medicine	Jun 07, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 20, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The HLCS c.782delG (p.Gly261ValfsTer20) variant is a frameshift variant that is predicted to cause premature truncation of the protein. The p.Gly261ValfsTer20 variant, described as one of the most common variants in the Japanese population in individuals with holocarboxylase synthetase (HLCS) deficiency, has been reported in three studies in which it is found in a total of nine patients with HLCS deficiency including in eight in a compound heterozygous state (of whom two are siblings) and in one in a heterozygous state in whom a second allele could not be identified based on screening of five variants (Suzuki et al. 1994; Yang et al. 2000; Yang et al. 2001; Castro et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.00035 in the East Asian population of the Exome Aggregation Consortium. Enzyme activity in patients ranged between 5-14% of the enzymatic activity of normal controls. The p.Gly261ValfsTer20 variant along with another missense variant was determined to be in linkage disequilibrium with a specific haplotype indicating that it is a founder variant in the Japanese population (Yang et al. 2000). Based on the evidence and potential impact of frameshift variants, the p.Gly261ValfsTer20 variant is classified as pathogenic for holocarboxylase synthetase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jul 22, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2000	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 20, 2024

Also known as delG1067; This variant is associated with the following publications: (PMID: 7842009, 35314707, 8541348, 11735028, 29961769, 9870216, 33514801) -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs771944310; hg19: chr21-38308962;