Submissions for variant NM_004168.4(SDHA):c.1660C>T (p.Arg554Trp)

gnomAD frequency: 0.00001  dbSNP: rs9809219

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000456631	SCV000553901	likely pathogenic	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 554 of the SDHA protein (p.Arg554Trp). This variant is present in population databases (rs9809219, gnomAD 0.01%). This missense change has been observed in individual(s) with mitochondrial complex II deficiency presenting as Leigh syndrome (PMID: 7550341). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8742). 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) has been performed at Invitae 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 affects SDHA function (PMID: 7550341, 16195397, 20489732, 22677546). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV000573113	SCV000664544	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-04-15	criteria provided, single submitter	clinical testing	The p.R554W variant (also known as c.1660C>T), located in coding exon 12 of the SDHA gene, results from a C to T substitution at nucleotide position 1660. The arginine at codon 554 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was detected in an individual with paraganglioma diagnosed before age 50 (Ambry internal data). This alteration has also been detected in a homozygous state in two siblings with Leigh syndrome and was found to have a deleterious effect on the catalytic activity of the SDH protein in yeast (Bourgeron T et al. Nat. Genet., 1995 Oct;11:144-9). Additional functional studies have shown that this alteration impairs SDHA protein activity (Mbaya E et al. Cell Death Differ., 2010 Dec;17:1855-66; Xiao M et al. Genes Dev., 2012 Jun;26:1326-38). This variant has been reported in conjunction with SDHA c.1549A>G in an 11 year old with dilated cardiomyopathy; however, authors did not comment on the phase of these alterations and no additional clinical information was provided (Gran F et al. Eur J Pediatr, 2022 Jan;181:287-294). 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.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000790927	SCV000930178	uncertain significance	Leigh syndrome	2019-04-27	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000009281	SCV000930179	uncertain significance	Mitochondrial complex II deficiency, nuclear type 1	2019-04-27	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818148	SCV002067388	likely pathogenic	not provided	2019-10-02	criteria provided, single submitter	clinical testing	DNA sequence analysis of the SDHA gene demonstrated a sequence change, c.1660C>T, in exon 12 that results in an amino acid change, p.Arg554Trp. The p.Arg554Trp change affects a highly conserved amino acid residue located in a domain of the SDHA protein that is known to be functional. This sequence change has been described in the gnomAD database with a population frequency of 0.014% in the Latino subpopulation (dbSNP rs9809219). The p.Arg554Trp substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL).
GeneDx	RCV001818148	SCV002574635	likely pathogenic	not provided	2022-09-13	criteria provided, single submitter	clinical testing	Functional analysis found R554W is associated with significantly reduced SDH activity (Bourgeron et al., 1995; Xiao et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 7550341, 11423010, 20489732, 22677546, 16195397, 1492653, 16798039, 21858060)
Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital	RCV003315222	SCV004012957	uncertain significance	Diffuse midline glioma, H3 K27-altered	2021-02-17	criteria provided, single submitter	research
Baylor Genetics	RCV003473060	SCV004200606	likely pathogenic	Dilated cardiomyopathy 1GG	2024-01-17	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000009281	SCV005398220	likely pathogenic	Mitochondrial complex II deficiency, nuclear type 1	2023-07-16	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with SDHA-related disorders. (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0112 - Variants in this gene are known to have reduced penetrance for paragangliomas 5 (PMID: 29978154). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2: 10 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 74 heterozygotes, 1 homozygote). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Succ_DH_flav_C domain (DECIPHER). (I) 0708 - Another missense variant comparable to the one identified in this case has conflicting previous evidence of pathogenicity. The p.(Arg554Gln) variant has been classified as a VUS, likely benign and benign in clinical cases in ClinVar. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has been identified as homozygous in two sisters diagnosed with Leigh syndrome (PMID: 7550341, PMID: 33162331). The variant has also been classified as likely pathogenic and a VUS in clinical cases in ClinVar. (SP) 0906 - Segregation evidence for this variant is inconclusive. The variant has been shown to segregate in one family with two affected siblings (PMID: 7550341). (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Complex II deficiency was shown in muscle, skin fibroblasts and lymphocytes from patient samples, as well as a deleterious effect on the catalytic activity of the SDH protein in yeast (PMID: 7550341, PMID: 20489732). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000009281	SCV000029499	pathogenic	Mitochondrial complex II deficiency, nuclear type 1	1995-10-01	no assertion criteria provided	literature only