ClinVar Miner

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

dbSNP: rs786205431
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Total submissions: 9
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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.
Invitae RCV000032616 SCV002218242 pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2023-07-17 criteria provided, single submitter clinical testing This variant is also known as F305 fs(-2) in literature. 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 premature translational stop signal has been observed in individual(s) with HMGCL-related conditions (PMID: 2443756, 6085636, 9463337). 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 2023-04-10 criteria provided, single submitter clinical testing
OMIM RCV000032616 SCV000056376 pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 1998-02-01 no assertion criteria provided literature only

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