Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000801921 | SCV000941724 | uncertain significance | Deficiency of 3-hydroxyacyl-CoA dehydrogenase | 2022-07-15 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 303 of the HADH protein (p.Gly303Val). This variant is present in population databases (rs575378007, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with HADH-related conditions. ClinVar contains an entry for this variant (Variation ID: 647412). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. |
| Gene |
RCV001577280 | SCV001804632 | pathogenic | not provided | 2021-01-29 | criteria provided, single submitter | clinical testing | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect |
| Clinical Genomics, |
RCV003222134 | SCV003915769 | likely risk allele | Hyperinsulinemic hypoglycemia | criteria provided, single submitter | research | Potent mutations in HADH gene are associated with congenital hyperinsulinism, which leads to recurrent hypoglycemia. The condition is exacerbated by stress, fasting or excessive dietary protein. May respond well to diazoxide. However, the role of this particular variant rs575378007 in congenital hyperinsulinism is yet to be ascertained. | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003387933 | SCV004099803 | uncertain significance | not specified | 2023-09-01 | criteria provided, single submitter | clinical testing | Variant summary: HADH c.908G>T (p.Gly303Val) results in a non-conservative amino acid change located in the 3-hydroxyacyl-CoA dehydrogenase, C-terminal (IPR006108) 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 251474 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. At least one non peer reviewed abstract reports four infant homozygotes with acyl-carnitine elevation confirmed by enzymatic studies, as well as western blot analysis confirming the absense of the protein (Feng_2019). However, in the absence of published peer reviewed reports, this does not provide unequivocal conclusions. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |