Submissions for variant NM_003001.5(SDHC):c.379C>G (p.His127Asp)

dbSNP: rs1485675090

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002352956	SCV002620134	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-27	criteria provided, single submitter	clinical testing	The p.H127D pathogenic mutation (also known as c.379C>G), located in coding exon 5 of the SDHC gene, results from a C to G substitution at nucleotide position 379. The histidine at codon 127 is replaced by aspartic acid, an amino acid with similar properties. This mutation has been detected in multiple individuals with paraganglioma(s) (Pczkowska M et al. Eur J Endocrinol, 2017 Feb;176:143-157; Ambry internal data). Another alteration at the same codon, p.H127R (c.380A>G), has been detected in multiple individuals with a paraganglioma, gastrointestinal stromal tumor, or renal carcinoma (Rattenberry E et al. J Clin Endocrinol Metab, 2013 Jul;98:E1248-56; Dénes J et al. J Clin Endocrinol Metab, 2015 Mar;100:E531-41; Gill AJ et al. Pathology, 2013 12;45:689-91; Casey RT et al. Sci Rep, 2019 07;9:10244). Based on internal structural analysis, p.H127D disrupts the SDHC heme-binding site, within which there are other internally pathogenic variants (Sun F et al. Cell, 2005 Jul;121:1043-57; Fufezan C et al. Proteins, 2008 Nov;73:690-704; Lemarie A et al. Mitochondrion, 2009 Jul;9:254-60). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003101258	SCV002977324	uncertain significance	Gastrointestinal stromal tumor; Paragangliomas 3	2023-05-10	criteria provided, single submitter	clinical testing	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. This variant disrupts the p.His127 amino acid residue in SDHC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22517557, 23162105, 24758179, 26273102, 30050099). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 SDHC protein function. ClinVar contains an entry for this variant (Variation ID: 1677290). This variant has not been reported in the literature in individuals affected with SDHC-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 127 of the SDHC protein (p.His127Asp).
All of Us Research Program, National Institutes of Health	RCV004005530	SCV004831442	likely pathogenic	Hereditary pheochromocytoma-paraganglioma	2023-06-26	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with aspartic acid at codon 127 of the SDHC 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, however other variants at this position (p.His127Ala and p.His127Tyr) were reported to completely abolished succinate ubiquinone oxidoreductase (SQR) and succinate dehydrogenase (SDH) activities of mitochondrial complex II, and rendered the SDHC protein unstable or degraded (PMID: 19332149). Another variant at this position has been classified as pathogenic in ClinVar (p.His127Arg) indicating that variants at this residue are disease causing (ClinVar Variation ID: 187084). This variant has been reported in individuals affected with paragangliomas (PMID: 27913608, 35171114). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV002223159	SCV005045698	likely pathogenic	Paragangliomas 3	2023-12-14	criteria provided, single submitter	clinical testing
Gemeinschaftspraxis fuer Humangenetik Dresden	RCV002223159	SCV002500061	likely pathogenic	Paragangliomas 3	2021-10-11	no assertion criteria provided	clinical testing	This mutation c.379C>G, p.(His127Asp) is not reported in HGMD 2021.2, gnomAD (v2.1.1), dbSNP (v151) or LOVD. But on same aminoacid position the pathogenic mutations p.(His127Tyr) and p.(His127Arg) for phenotype Phaeochromocytoma/paraganglioma are known. Multiple lines of computational evidence support a deleterious effect (SIFT, MutationTaster2021, PolyPhen-2). In summary, the p.(His127Asp) variant meets our criteria to be classified as likely pathogenic. ACMG: PM5, PM2, PP3 (ACMG Guidelines, 2015)