Submissions for variant NM_003172.4(SURF1):c.312_321delinsAT (p.Pro104_Leu105insTer) (rs863224228)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000197023	SCV000252354	pathogenic	not provided	2017-01-26	criteria provided, single submitter	clinical testing	The c.312_321del10insAT variant in the SURF1 gene is one of the most common pathogenic variants identified in patients with Leigh syndrome associated with COX deficiency (Wedatilake et al., 2013). The c.312_321del10insAT variant results in the deletion of 10 nucleotides and insertion of 2 nucleotides, which changes the codon Leucine 105 to a premature Stop codon, denoted p.L105X. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.312_321del10insAT variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.312_321del10insAT as a pathogenic variant.
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000235063	SCV000292355	pathogenic	Leigh syndrome	2015-08-18	criteria provided, single submitter	research	This variant is predicted deleterious according to ACMG guidelines. Identified with another predicted deleterious variant, in an individual with Leigh syndrome and peripheral neuropathy. Parents were not available for segregation; however, given the similarity of the phenotypic presentation to that reported in the literature, it is likely that two variants in SURF1 are causing the phenotype in this individual.
Invitae	RCV000235063	SCV000627065	pathogenic	Leigh syndrome	2019-01-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu105*) in the SURF1 gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported as homozygous or heterozygous in combination with another SURF1 variant in many individuals affected with Leigh syndrome (PMID: 9837813, 18804471, 23829769). This variant is also known as c.312del10,insAT in the literature. ClinVar contains an entry for this variant (Variation ID: 215237). Experimental studies have shown that this nonsense change decreases complex IV activity and oxygen consumption (PMID: 18804471). Loss-of-function variants in SURF1 are known to be pathogenic (PMID: 10443880, 22488715). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America	RCV000235063	SCV000698177	pathogenic	Leigh syndrome	2017-05-15	criteria provided, single submitter	clinical testing	Variant summary: The SURF1 c.312_321delinsAT (p.Leu105Terfs) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Gln251X, c.758_759delCA, c.845_846delCT, etc.). This variant is absent in 121016 control chromosomes from ExAC. This variant is the most common pathogenic variant in Caucasian Leigh syndrome cohorts (Lee_2012, Wedatilake_2013, Lim_2014). Numerous patients carrying this variant in homozygous state as well as compound heterozygous state with other pathogenic/likely pathogenic variants have been identified, including reports of cosegregation in families carrying this variant. Biochemical enzymatic analysis in patient cells carrying this variant are show impaired enzymatic activity (Tiranti_1998, Lim_2014). In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Fulgent Genetics,Fulgent Genetics	RCV000763191	SCV000893803	pathogenic	Leigh syndrome; Charcot-Marie-Tooth disease, type 4k	2018-10-31	criteria provided, single submitter	clinical testing
OMIM	RCV000013596	SCV000033843	pathogenic	Mitochondrial complex IV deficiency	2000-02-01	no assertion criteria provided	literature only