Submissions for variant NM_003000.3(SDHB):c.304G>A (p.Ala102Thr)

gnomAD frequency: 0.00003  dbSNP: rs777578399

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001018296	SCV001179515	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-13	criteria provided, single submitter	clinical testing	The p.A102T variant (also known as c.304G>A), located in coding exon 4 of the SDHB gene, results from a G to A substitution at nucleotide position 304. The alanine at codon 102 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in the homozygous state in an individual with Leigh syndrome (Kaur P et al. Ann Hum Genet, 2020 Jul;84:345-351). This alteration has also been reported in a breast cancer cohort from India (Mittal A et al. Ecancermedicalscience, 2022 Aug;16:1434). This amino acid position is highly conserved in available vertebrate species. 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.
GeneDx	RCV001766844	SCV002007880	uncertain significance	not provided	2020-07-28	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32124427)
Invitae	RCV001860902	SCV002282203	uncertain significance	Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma	2023-11-04	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 102 of the SDHB protein (p.Ala102Thr). This variant is present in population databases (rs777578399, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive mitochondrial complex II deficiency (PMID: 32124427). ClinVar contains an entry for this variant (Variation ID: 822717). 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) performed at Invitae indicates that this missense variant is expected to disrupt SDHB protein function with a positive predictive value of 80%. 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.
Arcensus	RCV001310281	SCV002564611	uncertain significance	Mitochondrial complex 2 deficiency, nuclear type 4	2013-02-01	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004004577	SCV004824962	uncertain significance	Hereditary pheochromocytoma-paraganglioma	2023-06-26	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 102 of the SDHB 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 paraganglioma or pheochromocytoma in the literature. This variant has been identified in 7/251406 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.
OMIM	RCV001310281	SCV001500014	pathogenic	Mitochondrial complex 2 deficiency, nuclear type 4	2021-03-08	flagged submission	literature only
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV001310281	SCV002053956	likely pathogenic	Mitochondrial complex 2 deficiency, nuclear type 4		flagged submission	research