Submissions for variant NM_000191.3(HMGCL):c.521G>A (p.Cys174Tyr)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV003468355	SCV004199904	likely pathogenic	Deficiency of hydroxymethylglutaryl-CoA lyase	2023-01-02	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV003468355	SCV005373664	pathogenic	Deficiency of hydroxymethylglutaryl-CoA lyase	2023-05-20	criteria provided, single submitter	clinical testing	The missense variant c.521G>A (p.Cys174Tyr) in the HMGCL gene has been reported previously in an individual affected with 3-hydroxy-3-methyl-glutaric aciduria (Menao et al., 2009). Experimental studies show a damaging effect. This variant is reported with the allele frequency (0.0003%) in the gnomAD Exomes. The amino acid Cysteine at position 174 is changed to a Tyrosine changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen - Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid change p.Cys174Tyr in HMGCL is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003468355	SCV005380890	likely pathogenic	Deficiency of hydroxymethylglutaryl-CoA lyase	2024-08-19	criteria provided, single submitter	clinical testing	Variant summary: HMGCL c.521G>A (p.Cys174Tyr) results in a non-conservative amino acid change located in the Pyruvate carboxyltransferase domain (IPR000891) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251330 control chromosomes. c.521G>A has been reported in the literature in a homozygous individual affected with HMG-CoA Lyase Deficiency (Menao_2008). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <5% of normal activity in an in vitro enzymatic activity assay (Menao_2008). ClinVar contains an entry for this variant (Variation ID: 2676033). Based on the evidence outlined above, the variant was classified as likely pathogenic.