rs1555882090

Positions:

• chr21-36756721-GGTA-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PM4_Supporting

The NM_001352514.2(HLCS):​c.2268_2270delTAC​(p.Thr757del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: HLCS NM_001352514.2 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 9.16

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001352514.2. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLCS	NM_001352514.2	c.2268_2270delTAC	p.Thr757del	disruptive_inframe_deletion	10/11	ENST00000674895.3	NP_001339443.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLCS	ENST00000674895.3	c.2268_2270delTAC	p.Thr757del	disruptive_inframe_deletion	10/11		NM_001352514.2	ENSP00000502087.2

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Holocarboxylase synthetase deficiency Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 13, 2023	This variant, c.1827_1829del, results in the deletion of 1 amino acid(s) of the HLCS protein (p.Thr610del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with holocarboxylase synthetase deficiency (PMID: 10190325). ClinVar contains an entry for this variant (Variation ID: 555891). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects HLCS function (PMID: 10190325, 24239178). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 02, 2018	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 04, 2023

Variant summary: HLCS c.1827_1829delTAC (p.Thr610del) results in an in-frame deletion that is predicted to remove one amino acids from the Biotinyl protein ligase (BPL) and lipoyl protein ligase (LPL), catalytic domain (IPR004143) of the encoded protein. The variant was absent in 251496 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1827_1829delTAC has been reported in the literature in a homozygous individual affected with late onset Holocarboxylase Synthetase Deficiency with mild phenotypes (example: Aoki_1999). These report(s) do not provide unequivocal conclusions about association of the variant with Holocarboxylase Synthetase Deficiency. Experimental studies have shown this variant had comparable activity to Wild-type protein (Aoki_1999 and Sakamoto_1999) but the Vmax was increased by ~3 fold ( Sakamoto_1999). Additionally, Trujillo-Gonzalez_2014 have shown that this variant fail to restore the biotinylation of acetyl-CoA carboxylase biotin carboxyl carrier protein (BCCP) at 42C using a bacterial expression vector. These results are not sufficient to conclusively determine the role of this variant in disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

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: rs1555882090; hg19: chr21-38129022;