ClinVar Miner

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

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Total submissions: 9
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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

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