ClinVar Genomic variation as it relates to human health

This variant is associated with the following publications: (PMID: 30094188, 20818383, 26764160)

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.

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.

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.

NDUFS8: BS2

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.

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).