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

dbSNP: rs863224228

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000197023	SCV000252354	pathogenic	not provided	2021-10-11	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22488715, 26257172, 23829769, 18804471, 29481804, 29715184, 32445240, 9837813)
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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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	RCV002478694	SCV000893803	pathogenic	Cytochrome-c oxidase deficiency disease; Charcot-Marie-Tooth disease type 4K	2021-07-29	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000197023	SCV002018892	pathogenic	not provided	2021-06-10	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000197023	SCV002051624	pathogenic	not provided	2021-03-08	criteria provided, single submitter	clinical testing	PVS1, PS3
Mayo Clinic Laboratories, Mayo Clinic	RCV000197023	SCV002520043	pathogenic	not provided	2021-04-27	criteria provided, single submitter	clinical testing	PVS1, PS3, PM2, PS4_supporting
CeGaT Center for Human Genetics Tuebingen	RCV000197023	SCV004032897	pathogenic	not provided	2023-08-01	criteria provided, single submitter	clinical testing	SURF1: PVS1, PM2, PM3, PS3:Supporting
PreventionGenetics, part of Exact Sciences	RCV003417716	SCV004112951	pathogenic	SURF1-related condition	2023-03-30	criteria provided, single submitter	clinical testing	The SURF1 c.312_321delinsAT variant is predicted to result in premature protein termination (p.Leu105*). This variant has previously been reported to be causative for Leigh syndrome due to cytochrome c oxidase (COX) deficiency (e.g., Tiranti et al. 1998. PubMed ID: 9837813; Marsy et al. 2008. PubMed ID: 18804471; Martin-Saavedra et al. 2021. PubMed ID: 34052969). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in SURF1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Invitae	RCV000235063	SCV004295604	pathogenic	Leigh syndrome	2024-01-25	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. Loss-of-function variants in SURF1 are known to be pathogenic (PMID: 10443880, 22488715, 24027061). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This premature translational stop signal has been observed in individuals with Leigh syndrome (PMID: 9837813, 18804471, 23829769). This variant is also known as c.312_321del10insAT. ClinVar contains an entry for this variant (Variation ID: 215237). For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000013596	SCV000033843	pathogenic	Cytochrome-c oxidase deficiency disease	2000-02-01	no assertion criteria provided	literature only