Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV002230665 | SCV000554067 | uncertain significance | Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas with sensorineural hearing loss; Cowden syndrome 3 | 2024-01-24 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 111 of the SDHD protein (p.Val111Ile). This variant is present in population databases (rs201869798, gnomAD 0.01%). This missense change has been observed in individual(s) with pheochromocytoma (PMID: 17308434, 24134185, 33219105). ClinVar contains an entry for this variant (Variation ID: 412515). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects SDHD function (PMID: 33219105). 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. |
| Ambry Genetics | RCV000565076 | SCV000675110 | likely benign | Hereditary cancer-predisposing syndrome | 2023-02-16 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
| Gene |
RCV001591105 | SCV001825380 | uncertain significance | not provided | 2023-05-10 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Functional studies demonstrate a damaging effect: decreased SDH activity (Kim et al., 2022); Also known as p.V55I; This variant is associated with the following publications: (PMID: 26273102, 17308434, 22904323, 33219105, 24134185, 32241160) |
| St. |
RCV003325203 | SCV004031142 | uncertain significance | Paragangliomas 1 | 2023-08-21 | criteria provided, single submitter | clinical testing | The SDHD c.331G>A (p.Val111Ile) missense change has a maximum subpopulation frequency of 0.011% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and a functional study has shown that this change affects SDHD function (PMID: 33219105). This variant has been reported in Korean and Japanese individuals with unilateral pheochromocytoma (PMID: 17308434, 24134185, 33219105). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. |
| Baylor Genetics | RCV003476144 | SCV004203107 | uncertain significance | Mitochondrial complex 2 deficiency, nuclear type 3 | 2023-06-15 | criteria provided, single submitter | clinical testing |