Submissions for variant NM_003172.4(SURF1):c.574_575insCTGC (p.Arg192fs)

dbSNP: rs782289759

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000478177	SCV000568229	pathogenic	not provided	2023-05-26	criteria provided, single submitter	clinical testing	Frameshift 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, 10443880, 24462369, 10556303, 15214016, 10746561, 36599233, 36463290, 34716721, 11317352, 29933018)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193160	SCV001361834	pathogenic	Leigh syndrome	2019-10-11	criteria provided, single submitter	clinical testing	Variant summary: SURF1 c.574_575insCTGC (p.Arg192ProfsX8) 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 4.4e-05 in 249494 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in SURF1 causing Leigh syndrome (4.4e-05 vs 0.0018), allowing no conclusion about variant significance. c.574_575insCTGC has been reported in the literature in individuals affected with Leigh syndrome (Lee_2012, Lim_2014). These data indicate that the variant is likely to be associated with disease. Two publication reported experimental evidence evaluating an impact on protein function and showed that this variant resulted in lower cytochrome c oxidase activity (Lee_2012, Lim_2014). 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 pathogenic.
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV001193160	SCV001423867	likely pathogenic	Leigh syndrome		criteria provided, single submitter	research	The SURF1 c.574_575insCTGC p.Arg192fs is a frameshift variant resulting in a premature stop codon eight amino acid residues downstream (p.Arg192ProfsTer8) in exon 6 of 9 total exons. Loss of normal protein function is predicted, either through nonsense-mediated mRNA decay or protein truncation. This variant has been reported in the compound heterozygous state with a second variant in at least six patients with SURF1-associated Leigh syndrome (PMID:10443880; 10746561; 22488715).
Mayo Clinic Laboratories, Mayo Clinic	RCV000478177	SCV001714334	pathogenic	not provided	2023-12-26	criteria provided, single submitter	clinical testing	PM2_moderate, PM3, PS4, PVS1
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002272252	SCV002557718	pathogenic	Mitochondrial complex IV deficiency, nuclear type 1	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with mitochondrial complex IV deficiency, nuclear type 1 (MIM#220110) and Charcot-Marie-Tooth disease, type 4K (MIM#616684). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (12 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported several times as pathogenic or likely pathogenic, and has been observed in multiple individuals with Leigh syndrome (ClinVar, PMID: 22488715). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV002272252	SCV002764919	pathogenic	Mitochondrial complex IV deficiency, nuclear type 1	2021-03-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001193160	SCV003253282	pathogenic	Leigh syndrome	2024-12-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg192Profs*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). This variant is present in population databases (rs782289759, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with Leigh syndrome (PMID: 10443880). This variant is also known as c.588insCTGC. ClinVar contains an entry for this variant (Variation ID: 419973). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV004965492	SCV005513517	pathogenic	Inborn genetic diseases	2024-11-25	criteria provided, single submitter	clinical testing	The c.574_575insCTGC (p.R192Pfs*8) alteration, located in exon 6 (coding exon 6) of the SURF1 gene, consists of an insertion of CTGC at position 574, causing a translational frameshift with a predicted alternate stop codon after 8 amino acids. Frameshift alterations are typically deleterious in nature (Richards, 2015). Based on data from gnomAD, the c.574_575insCTGC allele has an overall frequency of 0.004% (12/280900) total alleles studied. The highest observed frequency was 0.008% (10/128104) of European (non-Finnish) alleles. Based on the available evidence, this alteration is classified as pathogenic.