ClinVar Miner

Submissions for variant NM_000191.3(HMGCL):c.698A>G (p.His233Arg) (rs727503963)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000665316 SCV000789416 likely pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2017-02-07 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000153365 SCV000202849 pathogenic not provided 2014-01-23 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000665316 SCV000893291 pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000665316 SCV000919521 pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2018-01-15 criteria provided, single submitter clinical testing Variant summary: The HMGCL c.698A>G (p.His233Arg) variant involves the alteration of a conserved nucleotide that is located in the Pyruvate carboxyltransferase (InterPro) and is found in the active site required for Mg2+ binding (Fu_2006). 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 3/277164 control chromosomes at a frequency of 0.0000108, which does not exceed the estimated maximal expected allele frequency of a pathogenic HMGCL variant (0.0007071). The variant is reported in the literature as a homozygous and compound heterozygous allele in multiple patients, and functional studies show undetectable enzyme activity in the fibroblasts and lymphocytes of patients (Roberts_1996, Pospisilova_2003). In addition, one clinical diagnostic laboratory classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000665316 SCV000818257 pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2018-06-06 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 233 of the HMGCL protein (p.His233Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed as homozygous or on the opposite chromosome (in trans) from another pathogenic variant in individuals affected with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency (PMID: 9784232, 14518825). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 167180). Experimental studies have shown that this missense change impairs HMGCL enzymatic activity (PMID: 16330550, 8798725). For these reasons, this variant has been classified as Pathogenic.

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