ClinVar Miner

Submissions for variant NM_000191.3(HMGCL):c.206_207del (p.Ser69fs) (rs752137615)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000185970 SCV000238928 pathogenic not provided 2017-07-13 criteria provided, single submitter clinical testing The c.206_207delCT variant has been reported previously in association with HMG-CoA lyase deficiency (Mitchell et al., 1993; Menao et al. 2009). The c.206_207delCT variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The deletion causes a frameshift starting with codon Serine 69, changes this amino acid to a Cysteine residue and creates a premature Stop codon at position 11 of the new reading frame, denoted p.Ser69CysfsX11. This variant is predicted to cause loss of normal protein function either through premature protein truncation or nonsense-mediated mRNA decay. In summary, we interpret c.206_207delCT to be a pathogenic variant.
Counsyl RCV000012732 SCV000790562 likely pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2017-03-29 criteria provided, single submitter clinical testing
Invitae RCV000012732 SCV001381603 pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2019-10-03 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser69Cysfs*11) in the HMGCL gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs752137615, ExAC 0.02%). This variant has been observed to segregate with HMG-CoA lyase deficiency in a family (PMID: 8440722). ClinVar contains an entry for this variant (Variation ID: 11954). Loss-of-function variants in HMGCL are known to be pathogenic (PMID: 9817922, 17692550, 23465862). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000012732 SCV000032967 pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 1993-02-25 no assertion criteria provided literature only
Natera, Inc. RCV000012732 SCV001459894 pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2020-09-16 no assertion criteria provided clinical testing

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