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

dbSNP: rs752137615

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000185970	SCV000238928	pathogenic	not provided	2022-07-22	criteria provided, single submitter	clinical testing	Frameshift 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; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 8440722, 19177531, 35646072)
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	2024-01-14	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. Loss-of-function variants in HMGCL are known to be pathogenic (PMID: 9817922, 17692550, 23465862). This variant is present in population databases (rs752137615, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with HMG-CoA lyase deficiency (PMID: 8440722). It has also been observed to segregate with disease in related individuals. This variant is also known as S69fs(-2). ClinVar contains an entry for this variant (Variation ID: 11954). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000012732	SCV001983424	pathogenic	Deficiency of hydroxymethylglutaryl-CoA lyase	2021-09-09	criteria provided, single submitter	clinical testing	Variant summary: HMGCL c.206_207delCT (p.Ser69CysfsX11) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2.8e-05 in 251468 control chromosomes. c.206_207delCT has been reported in the literature in individuals affected with HMG-CoA Lyase Deficiency (e.g. Mitchell_1993). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Mitchell_1993). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV000012732	SCV004172714	pathogenic	Deficiency of hydroxymethylglutaryl-CoA lyase	2023-04-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000012732	SCV004199896	pathogenic	Deficiency of hydroxymethylglutaryl-CoA lyase	2024-02-29	criteria provided, single submitter	clinical testing
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