Submissions for variant NM_003172.4(SURF1):c.754_755del

dbSNP: rs782007828

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000312508	SCV000478286	likely pathogenic	Leigh syndrome	2017-04-27	criteria provided, single submitter	clinical testing	The SURF1 c.754_755delAG (p.Ser252HisfsTer39) variant, also known as c.752_753delAG, is a frameshift variant predicted to result in premature termination of the protein. The variant was first reported by Tanigawa et al. (2012) in a compound heterozygous state with a splice site variant in an individual with Leigh syndrome. Wedatilake et al. (2013) identified the c.754_755delAG variant in a homozygous state in one individual who had low muscle cytochrome c oxidase (COX) activity. Rodinová et al. (2014) described a third affected individual who was a compound heterozygote for the c.754_755delAG variant and another frameshift variant. The authors demonstrated that the amount and activity of complex IV (COX) in the fibroblasts of this patient was greatly reduced compared to that of healthy controls. Control data are unavailable for this variant, which is reported at a frequency of 0.00003 in the European (non-Finnish) population of the Exome Aggregation Consortium but this is from one allele in a region of low coverage. Based on the evidence from the literature and the potential impact of frameshift variants, the p.Ser252HisfsTer39 variant is interpreted as likely pathogenic for Leigh syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000312508	SCV001361830	pathogenic	Leigh syndrome	2021-12-06	criteria provided, single submitter	clinical testing	Variant summary: SURF1 c.754_755delAG (p.Ser252HisfsX39) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.5e-06 in 220304 control chromosomes. c.754_755delAG has been reported in the literature in multiple compound heterozygous and a homozygous individual affected with Leigh Syndrome (Tanigawa 2012, Wedatilake 2013, Rodinova 2014, Li 2018). These data indicate that the variant is likely to be associated with disease. Publications also reported that the variant results in low muscle cytochrome c oxidase (COX) activity in patients (Wedatilake 2013, Rodinova 2014). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000312508	SCV003507865	pathogenic	Leigh syndrome	2024-10-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser252Hisfs*39) in the SURF1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 49 amino acid(s) of the SURF1 protein. This variant is present in population databases (rs782007828, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with mitochondrial complex IV deficiency (PMID: 22410471, 30872186). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.752_753del. ClinVar contains an entry for this variant (Variation ID: 365526). This variant disrupts a region of the SURF1 protein in which other variant(s) (p.Ser282Cysfs*9) have been determined to be pathogenic (PMID: 9837813, 16326995, 18583168, 22488715, 23829769). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV003338577	SCV004047746	pathogenic	Mitochondrial complex IV deficiency, nuclear type 1		criteria provided, single submitter	clinical testing	The frameshift c.754_755del (p.Ser252HisfsTer39) variant has been reported in the literature in multiple compound heterozygous and a homozygous individual affected with Leigh Syndrome (Tanigawa J et al). This p.Ser252HisfsTer39 variant has allele frequency of 0.00045% in the gnomAD and novel (not in any individuals) in 1000 genome database. This variant has been reported to the ClinVar database as Pathogenic. This variant causes a frameshift starting with codon Serine 252, changes this amino acid to Histidine residue, and creates a premature Stop codon at position 39 of the new reading frame, denoted p.Ser252HisfsTer39. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV003338577	SCV005416338	pathogenic	Mitochondrial complex IV deficiency, nuclear type 1		criteria provided, single submitter	clinical testing	PM2_Supporting+PVS1+PM3_Strong+PP4