Submissions for variant NM_003002.4(SDHD):c.398C>A (p.Ala133Asp)

gnomAD frequency: 0.00002  dbSNP: rs755584530

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002230660	SCV000554051	uncertain significance	Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas with sensorineural hearing loss; Cowden syndrome 3	2023-12-15	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 133 of the SDHD protein (p.Ala133Asp). This variant is present in population databases (rs755584530, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with SDHD-related conditions. ClinVar contains an entry for this variant (Variation ID: 412502). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SDHD protein function. 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	RCV002356711	SCV002622469	uncertain significance	Hereditary cancer-predisposing syndrome	2024-06-21	criteria provided, single submitter	clinical testing	The p.A133D variant (also known as c.398C>A), located in coding exon 4 of the SDHD gene, results from a C to A substitution at nucleotide position 398. The alanine at codon 133 is replaced by aspartic acid, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV003476142	SCV004203103	uncertain significance	Mitochondrial complex 2 deficiency, nuclear type 3	2023-07-31	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004002009	SCV004829345	uncertain significance	Hereditary pheochromocytoma-paraganglioma	2024-07-29	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with aspartic acid at codon 133 of the SDHD protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with SDHD-related disorders in the literature. This variant has been identified in 4/249876 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.