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

gnomAD frequency: 0.00006  dbSNP: rs763494292

Total submissions: 12

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	2024-05-10	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000175544	SCV000954331	pathogenic	Deficiency of hydroxymethylglutaryl-CoA lyase	2024-09-04	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	2024-03-30	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