Submissions for variant NM_003172.4(SURF1):c.792_793del (p.Arg264fs)

dbSNP: rs782490558

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000198901	SCV000252355	pathogenic	not provided	2023-11-07	criteria provided, single submitter	clinical testing	Reported in two patients with Leigh syndrome who harbored different frameshift variants on the opposite allele (in trans) (PMID: 28639102); Frameshift variant predicted to result in protein truncation, as the last 37 amino acids are replaced with 26 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24462369, 10647889, 23829769, 26762927, 11409433, 31589614, 32907636, 36675121, 31965297, 33594065, 28639102)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000534608	SCV000627074	pathogenic	Leigh syndrome	2024-09-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg264Serfs*27) in the SURF1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 37 amino acid(s) of the SURF1 protein. This variant is present in population databases (rs782490558, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with cytochrome c oxidase (COX) deficient Leigh syndrome (PMID: 10647889, 23829769, 24462369). ClinVar contains an entry for this variant (Variation ID: 215238). This variant disrupts the p.Lys291* amino acid residue in SURF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9837813, 25111564, 27756633). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000534608	SCV000698183	pathogenic	Leigh syndrome	2017-08-10	criteria provided, single submitter	clinical testing	Variant summary: The SURF1 c.792_793delAG (p.Arg264Serfs) variant results in a premature termination codon, predicted to cause a truncated or absent SURF1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.845_846delCT, p.Ser282fs). One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/83140 control chromosomes at a frequency of 0.000012, which does not exceed the estimated maximal expected allele frequency of a pathogenic SURF1 variant (0.0017678). The variant was reported in the literature in numerous affected individuals, and two homozygous patients tested for fibroblast COX activity showed significantly reduced activity (Wedatilake_2013). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000198901	SCV000923666	pathogenic	not provided	2019-01-01	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV000534608	SCV002012056	pathogenic	Leigh syndrome	2021-10-02	criteria provided, single submitter	clinical testing	Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000219, PM2). The variant has been reported as pathogenic (ClinVar ID: SCV000033851). Patient's phenotype is considered compatible with Leigh syndrome, due to COX IV deficiency (3billion dataset, PP4). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
DASA	RCV001813769	SCV002061242	pathogenic	Charcot-Marie-Tooth disease type 4K	2022-01-05	criteria provided, single submitter	clinical testing	The c.792_793del;p.(Arg264Serfs*27) is a null frameshift variant (NMD) in the SURF1 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevantexon to the transcript - PVS1_strong. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 215238; PMID: 10647889;23829769; 24462369; 26341968) - PS4. The variant is present at low allele frequencies population databases (rs782490558– gnomAD 0.003291%; ABraOM 0.000427 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg264Serfs*27) was detected in trans with a pathogenic variant (PMID: 28639102) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic.
Ambry Genetics	RCV002517264	SCV003712698	pathogenic	Inborn genetic diseases	2021-04-02	criteria provided, single submitter	clinical testing	The c.792_793delAG (p.R264Sfs*27) alteration, located in exon 8 (coding exon 8) of the SURF1 gene, consists of a deletion of 2 nucleotides from position 792 to 793, causing a translational frameshift with a predicted alternate stop codon after 27 amino acids. This alteration occurs at the 3' terminus of the SURF1 gene and is not expected to trigger nonsense-mediated mRNA decay; however, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). Based on data from gnomAD, the c.792_793delAG allele has an overall frequency of <0.01% (6/273842) total alleles studied. The highest observed frequency was 0.01% (1/7068) of Other alleles. This mutation has been identified in the homozygous and compound heterozygous state in multiple individuals with SURF1-related mitochondrial complex IV deficiency (P&eacute;quignot, 2001; Wedatilake, 2013; Li, 2018; Tsang, 2020). Other truncating alterations downstream have been observed in individuals with a personal and/or family history that is consistent with SURF1-related mitochondrial complex IV deficiency (Tiranti, 1998; Piekutowska-Abramczuk, 2009). Based on the available evidence, this alteration is classified as pathogenic.
Revvity Omics, Revvity	RCV000198901	SCV003819787	pathogenic	not provided	2022-01-01	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000013605	SCV004048317	pathogenic	Mitochondrial complex IV deficiency, nuclear type 1		criteria provided, single submitter	clinical testing	The frameshift variant c.792_793del(p.Arg264SerfsTer27) in SURF1 gene has been reported in several individuals and families affected with cytochrome c oxidase (COX) deficient Leigh syndrome (Lim SC et.al.,2014). This variant has been reported to the ClinVar database as Pathogenic. The p.Arg264SerfsTer27 variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.002191% is reported in gnomAD. This variant causes a frameshift starting with codon Arginine 264, changes this amino acid to Serine residue, and creates a premature Stop codon at position 27 of the new reading frame, denoted p.Arg264SerfsTer27. For these reasons, this variant has been classified as Pathogenic
Illumina Laboratory Services, Illumina	RCV000013605	SCV004801513	pathogenic	Mitochondrial complex IV deficiency, nuclear type 1	2020-05-06	criteria provided, single submitter	clinical testing	Across a selection of the available literature, the SURF1 c.792_793delAG (p.Arg264SerfsTer27) variant, a frameshift variant, has been identified in at least seven unrelated individuals with Leigh syndrome, including in four in a homozygous state and three in a compound heterozygous state (Wedatilake et al. 2013; Sonam et al. 2017; Li et al. 2018). Clinical features of the probands included onset in infancy with poor feeding, vomiting, developmental regression, nystagmus, ophthalmoplegia, hypotonia, movement disorder, and respiratory failure (Wedatilake et al. 2013; Li et al. 2018). Fibroblast COX activity from two patients showed significantly reduced activity and COX histochemistry demonstrated reduced COX staining in muscle biopsies from four patients (Wedatilake et al. 2013). Control data are unavailable for this variant, which is reported at a frequency of 0.000022 in the Total population of the Genome Aggregation Database. Based on the collective evidence and application of the ACMG criteria, the c.792_793delAG (p.Arg264SerfsTer27) variant is classified as pathogenic for Mitochondrial complex IV deficiency.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000013605	SCV005416339	pathogenic	Mitochondrial complex IV deficiency, nuclear type 1		criteria provided, single submitter	clinical testing	PM2_Supporting+PVS1_Strong+PM3_VeryStrong+PP4
OMIM	RCV000013605	SCV000033851	pathogenic	Mitochondrial complex IV deficiency, nuclear type 1	2001-06-01	no assertion criteria provided	literature only