Submissions for variant NM_002496.4(NDUFS8):c.4C>T (p.Arg2Cys)

gnomAD frequency: 0.00205  dbSNP: rs150278938

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000726015	SCV000251921	likely benign	not provided	2020-12-21	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 30094188, 20818383, 26764160)
Eurofins Ntd Llc (ga)	RCV000726015	SCV000341244	uncertain significance	not provided	2016-04-08	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765008	SCV000896191	uncertain significance	Leigh syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000726015	SCV001039588	likely benign	not provided	2025-01-23	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001108403	SCV001265632	uncertain significance	Mitochondrial complex I deficiency, nuclear type 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV000765008	SCV001265633	uncertain significance	Leigh syndrome	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Ambry Genetics	RCV002517245	SCV003748369	likely benign	Inborn genetic diseases	2021-09-13	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
CeGaT Center for Human Genetics Tuebingen	RCV000726015	SCV004033144	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	NDUFS8: BS2
Baylor Genetics	RCV003458354	SCV004183525	uncertain significance	Mitochondrial complex 1 deficiency, nuclear type 2	2023-11-14	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000726015	SCV004226193	uncertain significance	not provided	2022-06-27	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000726015	SCV001552754	likely benign	not provided		no assertion criteria provided	clinical testing	The NDUFS8 p.Arg2Cys variant was identified in the literature in a case with Malignant Hyperthermia Susceptibility however this patient had variants in the HMBS and CACNA1S genes that were suspected to be the cause of the phenotype (Sambuughin_2018_PMID:30094188). The variant was identified in dbSNP (ID: rs150278938) and ClinVar (classified as uncertain significance by EGL Genetic Diagnostics, Fulgent Genetics, and GeneDx, and as likely benign by Invitae). The variant was identified in control databases in 481 of 282694 chromosomes (2 homozygous) at a frequency of 0.001701 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 394 of 129024 chromosomes (freq: 0.003054), Other in 9 of 7220 chromosomes (freq: 0.001247), African in 25 of 24970 chromosomes (freq: 0.001001), Latino in 25 of 35436 chromosomes (freq: 0.000706), European (Finnish) in 17 of 25118 chromosomes (freq: 0.000677), East Asian in 8 of 19952 chromosomes (freq: 0.000401) and South Asian in 3 of 30616 chromosomes (freq: 0.000098), but was not observed in the Ashkenazi Jewish population. The p.Arg2 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003907737	SCV004722728	likely benign	NDUFS8-related disorder	2019-12-11	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).