Submissions for variant NM_003172.4(SURF1):c.281dup (p.Leu94fs)

dbSNP: rs1588691786

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000797278	SCV000936827	pathogenic	Leigh syndrome	2023-09-21	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 643552). This premature translational stop signal has been observed in individual(s) with Leigh syndrome (PMID: 2933018, 24462369, 29933018, 32445240). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu94Phefs*8) in the SURF1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SURF1 are known to be pathogenic (PMID: 10443880, 22488715, 24027061).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000797278	SCV002819353	likely pathogenic	Leigh syndrome	2022-12-08	criteria provided, single submitter	clinical testing	Variant summary: SURF1 c.281dupT (p.Leu94PhefsX8) 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 was absent in 251306 control chromosomes (gnomAD). c.281dupT has been reported in the literature in individuals affected with Leigh Syndrome (examples: Alves_2020, Li_2018, and Lim_2014). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004554825	SCV004791875	pathogenic	SURF1-related disorder	2023-12-29	no assertion criteria provided	clinical testing	The SURF1 c.281dupT variant is predicted to result in a frameshift and premature protein termination (p.Leu94Phefs*8). This variant has been reported in the presumed compound heterozygous state in at least three individuals with Leigh syndrome (Lim et al. 2014. PubMed ID: 24462369; Li et al. 2018. PubMed ID: 29933018; Alves et al. 2020. PubMed ID: 32445240). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in SURF1 are expected to be pathogenic. This variant is interpreted as pathogenic.