Submissions for variant NM_003172.4(SURF1):c.563A>G (p.Asn188Ser)

gnomAD frequency: 0.00010  dbSNP: rs200702528

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000196814	SCV000252351	likely pathogenic	not provided	2013-10-01	criteria provided, single submitter	clinical testing	p.Asn188Ser (AAT>AGT): c.563 A>G in exon 6 of the SURF1 gene (NM_003172.2) The c.563 A>G sequence change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. Multiple in-silico splice prediction models predict that c.563 A>G creates a cryptic donor site, which would be expected to lead to abnormal gene splicing. However, the true effect of c.563 A>G on splicing in vivo is not known. Therefore, based on the currently available information, it is unclear whether c.563 A>G is a disease-causing mutation or a rare benign variant. The variant is found in MITONUC-MITOP panel(s).
Invitae	RCV001215689	SCV001387446	uncertain significance	Leigh syndrome	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 188 of the SURF1 protein (p.Asn188Ser). This variant is present in population databases (rs200702528, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with SURF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 215234). 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) performed at Invitae indicates that this missense variant is not expected to disrupt SURF1 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SURF1 function (PMID: 29933018). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222439	SCV002500642	uncertain significance	not specified	2022-03-25	criteria provided, single submitter	clinical testing	Variant summary: SURF1 c.563A>G (p.Asn188Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 249650 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in SURF1 causing Leigh Syndrome (0.00012 vs 0.0018), allowing no conclusion about variant significance. c.563A>G has been reported in the literature in a heterozygous individual affected with a suspected genetic disease (specific phenotype not provided) (Lazaridis_2016). This report does not provide unequivocal conclusions about association of the variant with Leigh Syndrome. Experimental evidence evaluating an impact on protein function showed that the variant decreases complex IV assembly without affecting SURF1 stability (Li_2018). This report does not allow convincing conclusions about the variant effect. A ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002517263	SCV003697804	uncertain significance	Inborn genetic diseases	2021-12-14	criteria provided, single submitter	clinical testing	Li, 2018 Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000196814	SCV001551334	uncertain significance	not provided		no assertion criteria provided	clinical testing	The SURF1 p.N188S variant was identified in dbSNP (ID: rs200702528) and ClinVar (classified as uncertain significance by Invitae and as likely pathogenic by GeneDx). The variant was identified in control databases in 31 of 281050 chromosomes at a frequency of 0.0001103 (Genome Aggregation Database March 6, 2019, v2.1.1). The p.N188 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen- 2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. Functional analysis suggests that this variant does not affect protein expression, but has mild effects on complex IV assembly (Li_2018_PMID: 29933018). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome and Splice AI genome) do not predict an effect on splicing. 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.¬â€