chr21-36756558-G-A
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_001352514.2(HLCS):c.2434C>T(p.Arg812Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000292 in 1,610,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R812R) has been classified as Likely benign.
Frequency
Consequence
NM_001352514.2 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HLCS | NM_001352514.2 | c.2434C>T | p.Arg812Ter | stop_gained | 10/11 | ENST00000674895.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HLCS | ENST00000674895.3 | c.2434C>T | p.Arg812Ter | stop_gained | 10/11 | NM_001352514.2 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000396 AC: 6AN: 151536Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251488Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135918
GnomAD4 exome AF: 0.0000281 AC: 41AN: 1459094Hom.: 0 Cov.: 33 AF XY: 0.0000289 AC XY: 21AN XY: 725944
GnomAD4 genome AF: 0.0000396 AC: 6AN: 151536Hom.: 0 Cov.: 31 AF XY: 0.0000406 AC XY: 3AN XY: 73976
ClinVar
Submissions by phenotype
Holocarboxylase synthetase deficiency Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 08, 2022 | Variant summary: HLCS c.1993C>T (p.Arg665X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. In at least one experimental study, a truncation downstream of this position was found to impair biotinylating activity, suggesting the C-terminal end of the protein is important for its functional activity (e.g. Campeau_2001). The variant allele was found at a frequency of 2.8e-05 in 251488 control chromosomes (gnomAD). c.1993C>T has been reported in the literature in individuals affected with Holocarboxylase Synthetase Deficiency (e.g. Suzuki 2005, Donti 2016, Tangeraas_2020). These data indicate that the variant is likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as likely pathogenic (n=3) or pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 20, 2021 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Dec 30, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 22, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change creates a premature translational stop signal (p.Arg665*) in the HLCS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 62 amino acid(s) of the HLCS protein. This variant is present in population databases (rs146448211, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with holocarboxylase synthetase deficiency (PMID: 16134170, 27114915, 33123633). ClinVar contains an entry for this variant (Variation ID: 203770). This variant disrupts the C-terminus of the HLCS protein. Other variant(s) that disrupt this region (p.Arg665Aspfs*41) have been observed in individuals with HLCS-related conditions (PMID: 10190325). This suggests that this may be a clinically significant region of the protein. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 20, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 16, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at