Submissions for variant NM_004589.4(SCO1):c.16C>G (p.Leu6Val)

dbSNP: rs61753148

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000128008	SCV000171598	benign	not specified	2014-04-08	criteria provided, single submitter	clinical testing	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.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224328	SCV000280709	likely benign	not provided	2015-08-19	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
Illumina Laboratory Services, Illumina	RCV000273401	SCV000400563	uncertain significance	Mitochondrial complex IV deficiency, nuclear type 1	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000273401	SCV000400564	uncertain significance	Mitochondrial complex IV deficiency, nuclear type 1	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000330754	SCV000400565	uncertain significance	Leigh syndrome	2018-01-12	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.
CeGaT Center for Human Genetics Tuebingen	RCV000224328	SCV000493162	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	SCO1: BP4, BS2
Labcorp Genetics (formerly Invitae), Labcorp	RCV000224328	SCV001094657	benign	not provided	2024-01-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000128008	SCV004020987	uncertain significance	not specified	2023-06-01	criteria provided, single submitter	clinical testing	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000224328	SCV000802734	uncertain significance	not provided	2016-02-22	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000224328	SCV001552024	uncertain significance	not provided		no assertion criteria provided	clinical testing	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.