Submissions for variant NM_000191.3(HMGCL):c.874_876+31del

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003006018	SCV003310841	pathogenic	Deficiency of hydroxymethylglutaryl-CoA lyase	2022-07-19	criteria provided, single submitter	clinical testing	Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. This variant disrupts a region of the HMGCL protein in which other variant(s) (p.Phe305Tyrfs*10) have been determined to be pathogenic (PMID: 2443756, 6085636, 9463337; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant has not been reported in the literature in individuals affected with HMGCL-related conditions. This variant is not present in population databases (gnomAD no frequency). This variant results in the deletion of part of exon 8 (c.874_876+31del) of the HMGCL gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product.