chr21-36765158-C-CA

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_001352514.2(HLCS):​c.1974dupT​(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

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:1

Conservation

PhyloP100: -1.40
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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: {Uncertain_significance=1, Pathogenic=5, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HLCSNM_001352514.2 linkc.1974dupT p.Val659CysfsTer65 frameshift_variant Exon 8 of 11 ENST00000674895.3 NP_001339443.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HLCSENST00000674895.3 linkc.1974dupT p.Val659CysfsTer65 frameshift_variant Exon 8 of 11 NM_001352514.2 ENSP00000502087.2 P50747-2A0A8C8QSB1

Frequencies

GnomAD3 genomes
AF:
0.0000854
AC:
13
AN:
152230
Hom.:
0
Cov.:
33
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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:7Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Holocarboxylase synthetase deficiency Pathogenic:5Uncertain:1
Jun 21, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Dec 13, 2018
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Jul 22, 2016
Counsyl
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 01, 2019
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Jun 13, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 12, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1
Sep 13, 2021
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Oct 02, 2023
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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

Name
Calibrated prediction
Score
Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs767533946; hg19: chr21-38137459; API