ClinVar Miner

Submissions for variant NM_000191.3(HMGCL):c.493C>T (p.Arg165Trp)

gnomAD frequency: 0.00002  dbSNP: rs764039230
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000674878 SCV001374871 likely pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2023-11-21 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 165 of the HMGCL protein (p.Arg165Trp). This variant is present in population databases (rs764039230, gnomAD 0.004%). This missense change has been observed in individual(s) with 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency (PMID: 10916782, 28583327). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 558583). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HMGCL protein function with a positive predictive value of 80%. This variant disrupts the p.Arg165 amino acid residue in HMGCL. Other variant(s) that disrupt this residue have been observed in individuals with HMGCL-related conditions (PMID: 19036343, 19932602), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Myriad Genetics, Inc. RCV000674878 SCV002060227 uncertain significance Deficiency of hydroxymethylglutaryl-CoA lyase 2022-01-04 criteria provided, single submitter clinical testing NM_000191.2(HMGCL):c.493C>T(R165W) is a missense variant classified as a variant of uncertain significance in the context of HMG-CoA lyase deficiency. R165W has been observed in cases with relevant disease (PMID: 28583327). Functional assessments of this variant are not available in the literature. R165W has been observed in population frequency databases (gnomAD: FIN 0.005%). In summary, there is insufficient evidence to classify NM_000191.2(HMGCL):c.493C>T(R165W) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Natera, Inc. RCV001830468 SCV002094161 likely pathogenic Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency 2020-01-16 no assertion criteria provided clinical testing

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