Submissions for variant NM_000191.3(HMGCL):c.914_915del (p.Phe305fs)

dbSNP: rs786205431

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724623	SCV000232919	pathogenic	not provided	2015-02-20	criteria provided, single submitter	clinical testing
Counsyl	RCV000032616	SCV000797207	pathogenic	Deficiency of hydroxymethylglutaryl-CoA lyase	2018-01-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000032616	SCV000919524	pathogenic	Deficiency of hydroxymethylglutaryl-CoA lyase	2018-09-24	criteria provided, single submitter	clinical testing	Variant summary: HMGCL c.914_915delTT (p.Phe305TyrfsX10) 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 7.2e-06 in 277236 control chromosomes. c.914_915delTT has been reported in the literature in two homozygous individuals affected with HMG-CoA Lyase Deficiency (Mitchell_1998). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000032616	SCV001367088	pathogenic	Deficiency of hydroxymethylglutaryl-CoA lyase	2020-02-03	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000032616	SCV002218242	pathogenic	Deficiency of hydroxymethylglutaryl-CoA lyase	2023-07-17	criteria provided, single submitter	clinical testing	This premature translational stop signal has been observed in individual(s) with HMGCL-related conditions (PMID: 2443756, 6085636, 9463337). This sequence change creates a premature translational stop signal (p.Phe305Tyrfs*10) in the HMGCL gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 21 amino acid(s) of the HMGCL protein. This variant is present in population databases (rs786205431, gnomAD 0.003%). This variant is also known as F305 fs(-2) in literature. ClinVar contains an entry for this variant (Variation ID: 31084). This variant disrupts the C-terminus of the HMGCL protein. Other variant(s) that disrupt this region (p.Gln308*) have been observed in individuals with HMGCL-related conditions (PMID: 11129331). This suggests that this may be a clinically significant region of the protein. For these reasons, this variant has been classified as Pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV000032616	SCV002557006	pathogenic	Deficiency of hydroxymethylglutaryl-CoA lyase	2020-11-23	criteria provided, single submitter	clinical testing	PVS1, PM2, PP5, PP4
Genome-Nilou Lab	RCV000032616	SCV004172647	pathogenic	Deficiency of hydroxymethylglutaryl-CoA lyase	2023-04-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000032616	SCV004199901	pathogenic	Deficiency of hydroxymethylglutaryl-CoA lyase	2024-03-04	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000032616	SCV004806887	pathogenic	Deficiency of hydroxymethylglutaryl-CoA lyase	2024-03-26	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000032616	SCV005647111	likely pathogenic	Deficiency of hydroxymethylglutaryl-CoA lyase	2024-06-18	criteria provided, single submitter	clinical testing
OMIM	RCV000032616	SCV000056376	pathogenic	Deficiency of hydroxymethylglutaryl-CoA lyase	1998-02-01	no assertion criteria provided	literature only