ClinVar Genomic variation as it relates to human health

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

SCO1: BP4, BS2

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.

Variant summary: SCO1 c.16C>G (p.Leu6Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0036 in 248192 control chromosomes in the gnomAD database, including 2 homozygotes. c.16C>G has been reported in the literature in individuals affected with Mitochondrial Complex 4 Deficiency without evidence for causality (e.g. McCormack_2016, Kumps_2021). These reports do not provide unequivocal conclusions about association of the variant with Mitochondrial Complex 4 Deficiency, Nuclear Type 4. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33340101; Book Chapter: doi.org/10.1016/B978-0-12-800877-5.00021-8). Four ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance, two as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as uncertain significance.

Converted during submission to Likely benign.

The SCO1 p.Leu6Val variant was not identified in the literature nor was it identified in the Cosmic database. The variant was identified in dbSNP (ID: rs61753148), ClinVar (reported as benign, likely benign and uncertain significance), Clinvitae, MutDB and LOVD 3.0. The variant was identified in control databases in 1015 of 279580 chromosomes (2 homozygous) at a frequency of 0.00363 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 818 of 126916 chromosomes (freq: 0.006445), Other in 25 of 7176 chromosomes (freq: 0.003484), Latino in 93 of 35346 chromosomes (freq: 0.002631), African in 39 of 24464 chromosomes (freq: 0.001594), South Asian in 26 of 30522 chromosomes (freq: 0.000852), European (Finnish) in 10 of 25074 chromosomes (freq: 0.000399), East Asian in 3 of 19798 chromosomes (freq: 0.000152), and Ashkenazi Jewish in 1 of 10284 chromosomes (freq: 0.000097). The p.Leu6 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, and MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.