ClinVar Miner

Submissions for variant NM_005276.4(GPD1):c.805C>T (p.Arg269Trp)

gnomAD frequency: 0.00003  dbSNP: rs761342764
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001926675 SCV002200132 uncertain significance not provided 2022-03-23 criteria provided, single submitter clinical testing In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with GPD1-related conditions. This variant is present in population databases (rs761342764, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 269 of the GPD1 protein (p.Arg269Trp).
PreventionGenetics, part of Exact Sciences RCV003416615 SCV004113058 pathogenic GPD1-related disorder 2023-06-27 criteria provided, single submitter clinical testing The GPD1 c.805C>T variant is predicted to result in the amino acid substitution p.Arg269Trp. This variant has been reported in the homozygous state in a patient with transient infantile hypertriglyceridemia (HTGTI) (Tan et al. 2022. PubMed ID: 36588760). Analysis of the crystal structure of GPD1 shows that the p.Arg269 residue is located in the center of the active site and disruption of this residue is expected to disrupt catalytic activity (Dionisi-Vici et al. 2016. PubMed ID: 27368975; Tan et al. 2022. PubMed ID: 36588760). This variant is reported in 0.020% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-50501542-C-T). At PreventionGenetics, we have detected this variant in the homozygous state in a patient with features consistent with HTGTI (Internal Data). Of note, another variant impacting the same amino acid (p.Arg269Gln) has also been reported in the homozygous state in a patient with HTGT1 (Patient A in Dionisi-Vici et al. 2016. PubMed ID: 27368975). Based on this evidence, we interpret the c.805C>T (p.Arg269Trp) variant as pathogenic.

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