Submissions for variant NM_001352514.2(HLCS):c.2121+1G>A

gnomAD frequency: 0.00003  dbSNP: rs1175936807

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000664724	SCV000788730	likely pathogenic	Holocarboxylase synthetase deficiency	2016-12-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000664724	SCV000915950	pathogenic	Holocarboxylase synthetase deficiency	2024-07-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000664724	SCV001577558	pathogenic	Holocarboxylase synthetase deficiency	2023-10-03	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 9 of the HLCS gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in HLCS are known to be pathogenic (PMID: 16134170). This variant is present in population databases (no rsID available, gnomAD 0.007%). Disruption of this splice site has been observed in individuals with holocarboxylase synthetase deficiency (PMID: 21615476; Invitae). This variant is also known as IVS9+1G>A. ClinVar contains an entry for this variant (Variation ID: 550091). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000664724	SCV003922653	likely pathogenic	Holocarboxylase synthetase deficiency	2023-03-30	criteria provided, single submitter	clinical testing	Variant summary: HLCS c.1680+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: four predict the variant abolishes a 5' splicing donor site, and two predict the variant strengthens a cryptic 5' donor site four nucleotides downstream, potentially leading to a frameshift. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251480 control chromosomes. c.1680+1G>A has been reported in the literature in at least one individual affected with Holocarboxylase Synthetase Deficiency (Esparza_2011). These data do not allow clear conclusions about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) have cited the variant with conflicting assessments: three submitters cite the variant as likely pathogenic, and one submitter cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV000664724	SCV004199857	likely pathogenic	Holocarboxylase synthetase deficiency	2024-03-27	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000664724	SCV002083726	likely pathogenic	Holocarboxylase synthetase deficiency	2020-03-29	no assertion criteria provided	clinical testing