Submissions for variant NM_003000.3(SDHB):c.221A>C (p.Asp74Ala)

gnomAD frequency: 0.00001  dbSNP: rs876658713

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000222241	SCV000274333	pathogenic	Hereditary cancer-predisposing syndrome	2024-07-23	criteria provided, single submitter	clinical testing	The c.221A>C (p.D74A) alteration is located in exon 3 (coding exon 3) of the SDHB gene. This alteration results from a A to C substitution at nucleotide position 221, causing the aspartic acid (D) at amino acid position 74 to be replaced by an alanine (A). Based on data from gnomAD, the C allele has an overall frequency of <0.001% (1/251336) total alleles studied. The highest observed frequency was 0.003% (1/34586) of Latino alleles. This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with SDHB-related disease and co-segregated with disease in at least one family (Greenberg, 2021; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000475368	SCV000554041	pathogenic	Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma	2024-11-03	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 74 of the SDHB protein (p.Asp74Ala). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individuals with paraganglioma (PGL), gastrointestinal stromal tumor, and renal cell carcinoma including SDH-deficient tumors ( (external communications, internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 230694). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SDHB protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001551663	SCV000605079	likely pathogenic	not provided	2022-02-11	criteria provided, single submitter	clinical testing	The SDHB c.221A>C; p.Asp74Ala variant (rs876658713) is reported in the literature in an individual affected with hereditary paraganglioma-pheochromocytoma syndrome (Greenberg 2020). This variant has also been observed in multiple patients affected with paraganglioma and renal cell carcinoma including SDH-deficient tumors at ARUP and other laboratories (external communications). This variant is also reported in ClinVar (Variation ID: 230694), but is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The aspartate at codon 74 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.939). Based on available information, this variant is considered to be likely pathogenic. References: Greenberg SE et al. Tumor detection rates in screening of individuals with SDHx-related hereditary paraganglioma-pheochromocytoma syndrome. Genet Med. 2020 Dec;22(12):2101-2107. PMID: 32741965.
GeneDx	RCV001551663	SCV001772221	pathogenic	not provided	2024-10-25	criteria provided, single submitter	clinical testing	Identified in individuals undergoing screening for Hereditary PGL/PCC syndrome in published literature (PMID: 32741965); Not observed at significant frequency in large population cohorts (gnomAD); 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: 34906457, 32741965)
Baylor Genetics	RCV003475010	SCV004202995	likely pathogenic	Gastrointestinal stromal tumor	2024-02-19	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV004556769	SCV005045795	likely pathogenic	Paragangliomas 4	2023-11-16	criteria provided, single submitter	clinical testing	The c.221A>C (p.Asp74Ala) variant in the SDHB gene is located on the exon 3 and is predicted to replace aspartic acid with alanine at codon 74 (p.Asp74Ala). The variant has been reported in individuals with paraganglioma/pheochromocytoma (PMID: 34255389, 34906457). The variant is reported to segregate with diseease by several ClinVar submitters (ID: 230694). The variant is rare in general population according to gnomAD (1/251336). Computational prediction algorithms suggest a deleterious impact for this variant (REVEL score 0.939). Therefore, the c.221A>C (p.Asp74Ala) variant of SDHB has been classified as likely pathogenic.
All of Us Research Program, National Institutes of Health	RCV004804876	SCV005424071	likely pathogenic	Hereditary pheochromocytoma-paraganglioma	2024-04-30	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with alanine at codon 74 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 been reported in individuals affected with paraganglioma (PGL), gastrointestinal stromal tumor (GIST), and renal cell carcinoma (RCC) (PMID: 34255389, ClinVar: SCV000274333, SCV001772221, SCV000605079). This variant has been identified in 1/251336 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.