ClinVar Miner

Submissions for variant NM_000191.3(HMGCL):c.505_506del (p.Ser169fs) (rs764264834)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000624137 SCV000742484 pathogenic Inborn genetic diseases 2017-05-18 criteria provided, single submitter clinical testing
Counsyl RCV000672012 SCV000797064 pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2018-01-10 criteria provided, single submitter clinical testing
Mendelics RCV000672012 SCV001135219 pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV000672012 SCV001417288 pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2020-08-03 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser169Leufs*8) in the HMGCL gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs764264834, ExAC 0.002%). This variant has been observed to be homozygous or in combination with another HMGCL variant in several individuals affected with HMG-CoA lyase deficiency (PMID: 9392428, 23465862). ClinVar contains an entry for this variant (Variation ID: 521753). Loss-of-function variants in HMGCL are known to be pathogenic (PMID: 9817922, 17692550, 23465862). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000672012 SCV001437216 pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2020-09-28 criteria provided, single submitter clinical testing Variant summary: HMGCL c.505_506delTC (p.Ser169LeufsX8) 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 (NMD), which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.2e-05 in 251290 control chromosomes (gnomAD). c.505_506delTC has been reported in the literature in multiple (compound heterozygote and homozygote) individuals affected with HMG-CoA Lyase Deficiency (Casals_1997, Cardoso_2004, Menao_2009, Puisac_2013). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, confirming that the variant results in NMD (Puisac_2013), with an activity in patient derived fibroblasts of less than 10% of the normal (Casals_1997, Cardoso_2004, Puisac_2013). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.