ClinVar Miner

Submissions for variant NM_000191.3(HMGCL):c.109G>T (p.Glu37Ter) (rs763494292)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000175544 SCV000790550 pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2017-03-28 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000400835 SCV000227048 pathogenic not provided 2014-12-04 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000175544 SCV000893292 pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000400835 SCV000329363 pathogenic not provided 2016-09-21 criteria provided, single submitter clinical testing The E37X pathogenic variant in the HMGCL gene has been reported previously in association with HMG-CoA lyase deficiency (Pie et al., 1997). E37X has been reported to alter an exon splice enhancer sequence, resulting in aberrant splicing with production of two protein products: one that has the skipping of exon 2, and a second that has a truncated 3-hydroxy-3- methylglutaryl-CoA lyase protein (Pie et al., 1997).
Illumina Clinical Services Laboratory,Illumina RCV000175544 SCV000915404 pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2018-08-09 criteria provided, single submitter clinical testing The HMGCL c.109G>T (p.Glu37Ter) variant is a stop-gained variant that is predicted to cause premature truncation of the protein. In a selection of the available literature, the p.Glu37Ter variant was found in at least 11 unrelated individuals affected with 3-hydroxy-3-methylglutaryl-Coenzyme A lyase deficiency, including in eight individuals in a homozygous state, in two in a compound heterozygous state and in one in a heterozygous state in whom the second variant was not found (Pié et al. 1997; Cardoso et al. 2004). The variant was shown to be absent from one control individual but is reported at a frequency of 0.000208 in the Latino population of the Genome Aggregation Database. In patiet fibroblasts, 3-hydroxy-3-methylglutaryl-Coenzyme A lyase activity was shown to be less than 3% of activity compared to the levels seen in healthy subjects (Pié et al. 1997; Cardoso et al. 2004). RT-PCR analysis in patient fibroblasts showed that the variant resulted in skipping of exon 2 (Pié et al. 1997). Based on the collective evidence and the potential impact of stop-gained variants, the p.Glu37Ter variant is classified as pathogenic for 3-hydroxy-3-methylglutaryl-Coenzyme A lyase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000175544 SCV000919523 pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2018-06-11 criteria provided, single submitter clinical testing Variant summary: HMGCL c.109G>T (p.Glu37X) 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. The variant allele was found at a frequency of 4.9e-05 in 246260 control chromosomes, which does not exceed the maximal expected allele frequency for a pathogenic variant in HMGCL. c.109G>T has been reported in the literature in multiple individuals affected with HMG-CoA Lyase Deficiency as both a homozygous and compound heterozygous allele. These data indicate that the variant is very likely to be associated with disease. In a report by Casale_1998, four patients homozygous for the variant had HMG-CoA lyase activity levels less than 10% of controls, indicating a severe reduction in enzyme activity caused by the variant. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000175544 SCV000954331 pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2018-12-05 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu37*) in the HMGCL gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 289 amino acids of the HMGCL protein. This variant is present in population databases (rs763494292, ExAC 0.009%). This variant has been observed in multiple individuals affected with HMG-CoA lyase deficiency (PMID: 28583327, 23465862, 19177531, 15308132). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 195033). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 23465862, 15752612). For these reasons, this variant has been classified as Pathogenic.

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