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

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000624533	SCV000742487	pathogenic	Inborn genetic diseases	2016-07-06	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
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
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000197896	SCV000345793	pathogenic	not provided	2016-09-02	criteria provided, single submitter	clinical testing
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.
Genetic Services Laboratory, University of Chicago	RCV000500935	SCV000597327	pathogenic	Charcot-Marie-Tooth disease, type 4k; Leigh syndrome due to COX IV deficiency	2016-07-29	criteria provided, single submitter	clinical testing
Institute of Human Genetics,Klinikum rechts der Isar	RCV000331329	SCV000680396	pathogenic	Leigh syndrome	2017-11-03	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.
Invitae	RCV000331329	SCV000752477	pathogenic	Leigh syndrome	2017-10-07	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.
OMIM	RCV000013608	SCV000033855	pathogenic	Leigh syndrome due to mitochondrial complex IV deficiency	2006-01-01	no assertion criteria provided	literature only