ClinVar Miner

Submissions for variant NM_001352514.2(HLCS):c.1960+5G>A (rs753887925)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000001989 SCV000795403 likely pathogenic Holocarboxylase synthetase deficiency 2017-11-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000001989 SCV000919518 pathogenic Holocarboxylase synthetase deficiency 2018-08-10 criteria provided, single submitter clinical testing Variant summary: HLCS c.1519+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant weakens a 5' donor site, while one predicts the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, with skipping of exon 10 in vitro and in a homozygous patient cell line (Sakamoto_2000). In addition, assays for HCS activity in these patient fibroblasts revealed levels at 4% of control activity. The variant allele was found at a frequency of 6.9e-05 in 277238 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in HLCS causing Holocarboxylase Synthetase Deficiency (6.9e-05 vs 0.0028), allowing no conclusion about variant significance. The variant, c.1519+5G>A, has been reported in the literature in multiple individuals affected with Holocarboxylase Synthetase Deficiency and is likely a Scandinavian founder mutation (Sakamoto_2000, Yang_2001). These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000001989 SCV000949761 pathogenic Holocarboxylase synthetase deficiency 2020-10-20 criteria provided, single submitter clinical testing This sequence change falls in intron 8 of the HLCS gene. It does not directly change the encoded amino acid sequence of the HLCS protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs753887925, ExAC 0.02%). This variant has been observed to be homozygous or in combination with another HLCS variant in several individuals affected with holocarboxylase synthetase defficiency (PMID: 10653324, 11735028, 27114915). This variant is also known as IVS10+5G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 1912). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing and is expected to lead to the loss of protein expression (PMID: 10653324). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001566943 SCV001790534 pathogenic not provided 2020-04-07 criteria provided, single submitter clinical testing Intronic +5 splice site variant in a gene for which loss-of-function is a known mechanism of disease, and both in silico predictors and evolutionary conservation support a deleterious effect; This variant is associated with the following publications: (PMID: 27114915, 16134170, 11735028, 10653324, 25525159)
OMIM RCV000001989 SCV000022147 pathogenic Holocarboxylase synthetase deficiency 2001-11-01 no assertion criteria provided literature only
Natera, Inc. RCV000001989 SCV001456938 pathogenic Holocarboxylase synthetase deficiency 2020-09-16 no assertion criteria provided clinical testing

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