Submissions for variant NM_003172.4(SURF1):c.841_842CT[2] (p.Ser282fs) (rs782316919)

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000197896	SCV000252357	pathogenic	not provided	2017-01-27	criteria provided, single submitter	clinical testing	The c.845_846delCT pathogenic variant in the SURF1 gene has been reported previously either as a homozygous variant or with another SURF1 variant in multiple individuals with COX deficient Leigh syndrome (Tiranti et al., 1998; Bohm et al., 2006). The c.845_846delCT variant causes a frameshift starting with codon Serine 282, changes this amino acid to a Cysteine residue, and creates a premature Stop codon at position 9 of the new reading frame, denoted p.Ser282CysfsX9. This variant is predicted to cause loss of normal protein function through protein truncation. The c.845_846delCT variant was not observed with any significant frequency in the Exome Aggregation Consortium (ExAC) data set, indicating it is not a common benign variant. We interpret c.845_846delCT as a pathogenic variant.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000197896	SCV000345793	pathogenic	not provided	2016-09-02	criteria provided, single submitter	clinical testing
Genetic Services Laboratory,University of Chicago	RCV000500935	SCV000597327	pathogenic	Leigh syndrome due to mitochondrial complex IV deficiency; Charcot-Marie-Tooth disease, type 4k	2016-07-29	criteria provided, single submitter	clinical testing
Institute of Human Genetics,Klinikum rechts der Isar	RCV000331329	SCV000680396	pathogenic	Leigh syndrome	2018-01-12	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000331329	SCV000698184	pathogenic	Leigh syndrome	2016-10-06	criteria provided, single submitter	clinical testing	Variant summary: The SURF1 c.845_846delCT (p.Ser282Cysfs) 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. One in silico tool predicts a damaging outcome for this variant. This variant was found in 19/120666 control chromosomes at a frequency of 0.0001575, which does not exceed the estimated maximal expected allele frequency of a pathogenic SURF1 variant (0.0017678). The variant has been reported in numerous affected individuals in the literature, both in the homozygous and compound heterozygous state. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Ambry Genetics	RCV000624533	SCV000742487	pathogenic	Inborn genetic diseases	2016-07-06	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana	RCV000626844	SCV000747547	pathogenic	Cerebellar ataxia; Muscle weakness; Dysarthria; Abnormal pyramidal signs	2017-01-01	criteria provided, single submitter	clinical testing
Invitae	RCV000331329	SCV000752477	pathogenic	Leigh syndrome	2019-09-06	criteria provided, single submitter	clinical testing	This sequence change results in a premature translational stop signal in the SURF1 gene (p.Ser282Cysfs*9). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 19 amino acids of the SURF1 protein. This variant is present in population databases (rs782316919, ExAC 0.02%). This variant has been reported as homozygous or compound heterozygous with a second rare SURF1 variant in many individuals affected with autosomal recessive Leigh disease (PMID: 9837813, 18583168, 22488715,23829769, 16326995) and is considered one of the most common variants causing SURF1 deficient Leigh disease (PMID: 16326995, 18583168). ClinVar contains an entry for this variant (Variation ID: 12770). For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000197896	SCV001246374	pathogenic	not provided	2019-06-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana	RCV000331329	SCV001370098	pathogenic	Leigh syndrome	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic.
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	RCV000013608	SCV001441582	pathogenic	Mitochondrial complex IV deficiency		criteria provided, single submitter	clinical testing	Evaluation: The homozygous deletion of the 2 bases AG at position 136218825 on Chr 9 was is covered with 155 reads and is found in 90% of the reads. Both parents are heterozygous carriers of the deletion at this position (cover 101 Reads in the father and 45% of the reads show the deletion, 112 reads in the mother and 40% show the deletion). This variant leads to a shift of the reading frame from position 282 followed by a stop codon after nine amino acids. To bioinformatic prediction, this variant leads to the loss of function of SURF1 and is therefore classified as pathogenic. This variant is classified according to ACMG guidelines are also classified as pathogenic. Classification according to ACMG guidelines of c.845_846delCT: - PVS1: The variant leads to a loss of function of the gene or gene product . - PM2: The variant was only tested with a very low frequency in population genetic studies. (like GnomAD, Iranome, GME, 1kGP, etc.) identified, and not in homozygous state observed. - PM3: The variant is homozygous in a recessively inherited disease. - PP3: Bioinformatic prediction programs such as GERP and MutationTaster grade this variant as pathogenic. - PP5: In ClinVar this variant is classified as pathogenic: https://www.ncbi.nlm.nih.gov/ Clinvar/RCV000331329/ The SURF1 gene encodes part of the assembly factor of the mitochondrial complex IV (COX), which is found in of the inner mitochondrial membrane and is involved in the biogenesis of cytochrome C oxidase complex is involved. Mutations in SURF1 (MIM#185620) are observed in patients with the recessively inherited nuclear mitochondrial complexes IV deficiency, type 1 (MIM#220110), which has been clinically described as Leigh Syndrome can manifest. In a review by Wedatilake et al (2013), a patient (27) with developmental delay hypotension, poor food intake, failure to thrive (poor weight gain) and developmental regression and respiratory insufficiency, which has the same variant (c.845_846delCT) in compound heterozygosity with a splice mutation.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000197896	SCV001448068	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
OMIM	RCV000013608	SCV000033855	pathogenic	Mitochondrial complex IV deficiency	2006-01-01	no assertion criteria provided	literature only