ClinVar Miner

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

gnomAD frequency: 0.00006  dbSNP: rs763494292
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000400835 SCV000227048 pathogenic not provided 2014-12-04 criteria provided, single submitter clinical testing
GeneDx RCV000400835 SCV000329363 pathogenic not provided 2023-06-01 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 19177531, 15752612, 18080783, 25525159, 9439591, 15308132, 17692550, 28583327, 28257639, 31589614, 28396157, 9163320, 23465862)
Fulgent Genetics, Fulgent Genetics RCV000175544 SCV000893292 pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2021-10-04 criteria provided, single submitter clinical testing
Illumina Laboratory Services, 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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 2023-12-03 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 acid(s) of the HMGCL protein. This variant is present in population databases (rs763494292, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with HMG-CoA lyase deficiency (PMID: 15308132, 19177531, 23465862, 28583327). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 195033). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV002516681 SCV003744698 pathogenic Inborn genetic diseases 2021-06-18 criteria provided, single submitter clinical testing The c.109G>T (p.E37*) alteration, located in exon 2 (coding exon 2) of the HMGCL gene, consists of a G to T substitution at nucleotide position 109. This changes the amino acid from a glutamic acid (E) to a stop codon at amino acid position 37. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This mutation has been report in several homozygous and compound heterozygous individuals with HMG-CoA lyase deficiency (Pié, 1997; Cardoso, 2004; Menao, 2009; Muñoz-Bonet, 2017). Analysis of patient fibroblasts demonstrated that this mutation resulted in exon 2 skipping (Puisac, 2013). Based on the available evidence, this alteration is classified as pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV000175544 SCV003807238 pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2023-01-06 criteria provided, single submitter clinical testing ACMG classification criteria: PVS1 very strong, PM2 supporting, PM3 strong, PP4
Genome-Nilou Lab RCV000175544 SCV004172792 pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2023-04-11 criteria provided, single submitter clinical testing
Baylor Genetics RCV000175544 SCV004199883 pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2023-10-12 criteria provided, single submitter clinical testing
Counsyl RCV000175544 SCV000790550 pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2017-03-28 no assertion criteria provided clinical testing
Natera, Inc. RCV000175544 SCV001459895 pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2020-09-16 no assertion criteria provided clinical testing

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