Submissions for variant NM_003172.4(SURF1):c.773_774del (p.Pro258fs)

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	RCV002281857	SCV002572392	pathogenic	Leigh syndrome	2022-08-28	criteria provided, single submitter	clinical testing	Variant summary: SURF1 c.773_774delCC (p.Pro258HisfsX33) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4.2e-06 in 236592 control chromosomes. c.773_774delCC has been reported in the literature in individuals affected with Leigh Syndrome (example, Rossi_2003, Tiranti_1998). 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	RCV002281857	SCV003242961	pathogenic	Leigh syndrome	2023-08-05	criteria provided, single submitter	clinical testing	This premature translational stop signal has been observed in individual(s) with clinical features of Leigh disease (PMID: 9837813). 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.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. ClinVar contains an entry for this variant (Variation ID: 1705227). This variant is also known as 772delCC. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Pro258Hisfs*33) in the SURF1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 43 amino acid(s) of the SURF1 protein.