Submissions for variant NM_004168.4(SDHA):c.512G>A (p.Arg171His)

gnomAD frequency: 0.00003  dbSNP: rs587782076

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130572	SCV000185444	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-07-06	criteria provided, single submitter	clinical testing	The p.R171H variant (also known as c.512G>A), located in coding exon 5 of the SDHA gene, results from a G to A substitution at nucleotide position 512. The arginine at codon 171 is replaced by histidine, an amino acid with highly similar properties. This alteration has been identified in multiple individuals diagnosed with a pheochromocytoma and/or paraganglioma (Ambry internal data; Benn DE et al. J. Med. Genet., 2018 11;55:729-734). This alteration was also identified in an individual with a gastrointestinal stromal tumor (Pantaleo MA et al. Front Oncol, 2021 Jan;11:778461). 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 majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000466700	SCV000553908	uncertain significance	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5	2024-12-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 171 of the SDHA protein (p.Arg171His). This variant is present in population databases (rs587782076, gnomAD 0.008%). This missense change has been observed in individual(s) with gastrointestinal stromal tumor, paraganglioma, and/or pheochromocytoma (PMID: 30201732, 35059314). ClinVar contains an entry for this variant (Variation ID: 141875). 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) has been performed 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 SDHA protein function. Experimental studies have shown that this missense change does not substantially affect SDHA function (PMID: 28724664). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000512840	SCV000609153	uncertain significance	not provided	2017-06-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001153307	SCV001314586	uncertain significance	Mitochondrial complex II deficiency, nuclear type 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001153308	SCV001314587	uncertain significance	Leigh syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001153309	SCV001314588	uncertain significance	Hereditary pheochromocytoma-paraganglioma	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
“Giorgio Prodi” Cancer Research Center, University of Bologna	RCV001799623	SCV002026139	uncertain significance	Gastrointestinal stromal tumor	2021-10-01	criteria provided, single submitter	research
Baylor Genetics	RCV003474764	SCV004202383	uncertain significance	Dilated cardiomyopathy 1GG	2023-10-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000512840	SCV005333047	uncertain significance	not provided	2024-03-20	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest a neutral effect: demonstrates normal growth phenotype, protein abundance and catalytic activity comparable to wild type in a yeast-based assay (PMID: 28724664); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 35982160, 30201732, 35982159, 35059314, 28724664)
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV004786391	SCV005402319	uncertain significance	Paragangliomas 5	2024-02-11	criteria provided, single submitter	clinical testing	The SDHA c.512G>A (p.Arg171His) missense change has a maximum subpopulation frequency of 0.008% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in individuals with SDHA-related tumors (PMID: 30201732, 30616628). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.