ClinVar Miner

Submissions for variant NM_000191.3(HMGCL):c.121C>T (p.Arg41Ter)

gnomAD frequency: 0.00001  dbSNP: rs770225915
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000669475 SCV000794232 likely pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2017-09-20 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000669475 SCV001226815 pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2023-05-11 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 553933). This premature translational stop signal has been observed in individual(s) with HMG-CoA lyase deficiency (PMID: 9463337). This variant is present in population databases (rs770225915, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg41*) in the HMGCL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HMGCL are known to be pathogenic (PMID: 9817922, 17692550, 23465862).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000669475 SCV002500654 likely pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2022-03-26 criteria provided, single submitter clinical testing Variant summary: HMGCL c.121C>T (p.Arg41X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251480 control chromosomes. c.121C>T has been reported in the literature without a second allele identified in at-least one individual affected with HMG-CoA Lyase Deficiency (example, Mitchell_1998 cited in Menao_2009). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three 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 likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000669475 SCV002769235 pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2020-05-21 criteria provided, single submitter clinical testing A homozygous nonsense variant was identified, NM_000191.2(HMGCL):c.121C>T in exon 2 of 9 of the HMGCL gene. This nonsense variant is predicted to create a change of an arginine to a stop at amino acid position 41 of the protein; NP_000182.2(HMGCL):p.(Arg41*), resulting in the loss of normal protein function through nonsense-mediated decay (NMD). The variant is present in the gnomAD population database at a frequency of 0.0004% (1 heterozygote, 0 homozygotes) and has been previously identified in patients with HMG-CoA lyase deficiency (ClinVar, Mitchell G. et al. (1998)). Other variants predicted to cause NMD have been reported as pathogenic in individuals with HMG-CoA lyase deficiency (ClinVar). Based on information available at the time of curation, this variant has been classified as PATHOGENIC. Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Fulgent Genetics, Fulgent Genetics RCV000669475 SCV002786742 likely pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2022-01-18 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000669475 SCV004172781 pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2023-04-11 criteria provided, single submitter clinical testing
Baylor Genetics RCV000669475 SCV004199891 pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2023-11-21 criteria provided, single submitter clinical testing
Natera, Inc. RCV001829857 SCV002094169 likely pathogenic Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency 2021-02-08 no assertion criteria provided clinical testing

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