Submissions for variant NM_003172.4(SURF1):c.817C>T (p.Gln273Ter)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155662	SCV003844422	pathogenic	Leigh syndrome	2023-02-07	criteria provided, single submitter	clinical testing	Variant summary: SURF1 c.817C>T (p.Gln273X) results in a premature termination codon, predicted to cause a truncation of the encoded protein which is a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8.1e-06 in 245476 control chromosomes (gnomAD). c.817C>T has been reported in the literature in two homozygous siblings affected with Leigh Syndrome, whose parents were both unaffected heterozygous carriers (Dixon-Salazar_2012). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003155662	SCV004295596	pathogenic	Leigh syndrome	2023-08-07	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the SURF1 protein in which other variant(s) (p.Val276Cysfs*5) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 2445743). This premature translational stop signal has been observed in individual(s) with mitochondrial complex IV deficiency (PMID: 22700954). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs782076866, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Gln273*) in the SURF1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 28 amino acid(s) of the SURF1 protein.