Submissions for variant NM_017841.4(SDHAF2):c.25A>G (p.Thr9Ala)

dbSNP: rs1554983610

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000547322	SCV000637889	uncertain significance	Hereditary pheochromocytoma-paraganglioma	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 9 of the SDHAF2 protein (p.Thr9Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SDHAF2-related conditions. ClinVar contains an entry for this variant (Variation ID: 463820). 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 alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.
Sema4, Sema4	RCV002255443	SCV002527226	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-26	criteria provided, single submitter	curation
Ambry Genetics	RCV002255443	SCV002743022	likely benign	Hereditary cancer-predisposing syndrome	2022-03-08	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Baylor Genetics	RCV003476258	SCV004202943	uncertain significance	Paragangliomas 2	2023-08-11	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000547322	SCV004826368	uncertain significance	Hereditary pheochromocytoma-paraganglioma	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 9 of the SDHAF2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with SDHAF2-related disorders in the literature. This variant has not been identified 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.