Submissions for variant NM_000191.3(HMGCL):c.853del (p.Met284_Leu285insTer)

gnomAD frequency: 0.00006  dbSNP: rs779339230

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000778975	SCV000915403	uncertain significance	Deficiency of hydroxymethylglutaryl-CoA lyase	2018-01-24	criteria provided, single submitter	clinical testing	The HMGCL c.853delC (p.Leu285Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The variant has been reported in one study in which it is found in a compound heterozygous state in one individual with 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency (Menao et al. 2009). The proband presented with acute disease with hypoketotic hypoglycemia and metabolic acidosis. Control data are unavailable for this variant, which is reported at a frequency of 0.000055 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the evidence and the potential impact of frameshift variants, the p.Leu285Ter variant is classified as a variant of unknown significance but suspicious for pathogenicity 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.
Invitae	RCV000778975	SCV001219574	pathogenic	Deficiency of hydroxymethylglutaryl-CoA lyase	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu285*) 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). This variant is present in population databases (rs779339230, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with HMG-CoA lyase deficiency (PMID: 19177531). ClinVar contains an entry for this variant (Variation ID: 632104). This variant disrupts a region of the HMGCL protein in which other variant(s) (p.Phe305Tyrfs*10) have been determined to be pathogenic (PMID: 2443756, 6085636, 9463337). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000778975	SCV001361813	likely pathogenic	Deficiency of hydroxymethylglutaryl-CoA lyase	2022-03-04	criteria provided, single submitter	clinical testing	Variant summary: HMGCL c.853delC (p.Leu285X) results in a premature termination codon in exon 8 (i.e. in the penultimate exon), resulting in a premature termination codon that is not expected to cause nonsense mediated decay (NMD), but is predicted to cause a truncation of the encoded protein, removing a part of the Pyruvate carboxyltransferase domain (amino acids 32-306; IPR000891). A truncation downstream of this position (c.914_915delTT, p.Phe305TyrfsX10) has been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 3.2e-05 in 251464 control chromosomes (gnomAD). c.853delC has been reported in the literature in at least one compound heterozygous individual affected with HMG-CoA Lyase Deficiency (Menao_2009). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters have assessed the variant since 2014: two have classified the variant as likely pathogenic and one as of uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003411719	SCV004116145	likely pathogenic	HMGCL-related condition	2022-11-02	criteria provided, single submitter	clinical testing	The HMGCL c.853delC variant is predicted to result in premature protein termination (p.Leu285*). This variant was reported in the compound heterozygous state in an individual with 3-hydroxy-3-methylglutaric aciduria (Menao et al. 2009. PubMed ID: 19177531). This variant is reported in 0.0054% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-24130912-AG-A). Nonsense variants in HMGCL are expected to be pathogenic. This variant is interpreted as likely pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV000778975	SCV004175457	likely pathogenic	Deficiency of hydroxymethylglutaryl-CoA lyase	2022-03-25	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000778975	SCV004199885	pathogenic	Deficiency of hydroxymethylglutaryl-CoA lyase	2023-10-11	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000778975	SCV001459890	likely pathogenic	Deficiency of hydroxymethylglutaryl-CoA lyase	2020-09-16	no assertion criteria provided	clinical testing