Submissions for variant NM_003172.4(SURF1):c.758_759del (p.Thr253fs)

dbSNP: rs782349178

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413343	SCV000491134	pathogenic	not provided	2024-07-25	criteria provided, single submitter	clinical testing	Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 48 amino acids are lost and replaced with 37 incorrect amino acids (HGMD); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11317352, 23829769, 10443880, 16326995, 21611066, 22310368, 29933018)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586290	SCV000698182	pathogenic	Leigh syndrome	2016-02-12	criteria provided, single submitter	clinical testing	Variant summary: SURF1 c.758_759delCA variant results in a premature termination codon, predicted to cause a truncated or absent SURF1 protein, which is a commonly known mechanism for Leigh Syndrome. Mutation Taster predicts a damaging outcome for this variant, and functional studies from patient fibroblasts (homozygous and compound heterozygous) with this variant show severely impaired complex IV activity. The variant of interest was found in the large, broad control population, ExAC, with an allele frequency of 3/62366 (1/20790), which does not exceed the maximum expected allele frequency for a pathogenic SURF1 variant of 1/565. The variant of interest has been reported in multiple Leigh Syndrome patients in the literature. Taken together, this is a disease variant and was classified as pathogenic.
Revvity Omics, Revvity	RCV000413343	SCV002018893	pathogenic	not provided	2021-08-31	criteria provided, single submitter	clinical testing
DASA	RCV001849366	SCV002107082	pathogenic	Mitochondrial complex IV deficiency, nuclear type 1	2022-03-05	criteria provided, single submitter	clinical testing	The c.758_759delCA;p.(Thr253Serfs*38) is a null frameshift variant (NMD) in the SURF1 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 372717; PMID: 24462369; PMID: 22310368; PMID: 21611066) - PS4. The variant is present at low allele frequencies population databases (rs782349178 – gnomAD 0.0001582%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Thr253Serfs*38) was detected in trans with a pathogenic variant (PMID: 24462369; PMID: 22310368; PMID: 21611066) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000586290	SCV002247397	pathogenic	Leigh syndrome	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr253Serfs*38) in the SURF1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 48 amino acid(s) of the SURF1 protein. 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 premature translational stop signal has been observed in individual(s) with clinical features of Leigh syndrome (PMID: 10443880). This variant disrupts a region of the SURF1 protein in which other variant(s) (p.Arg264Serfs*27) have been determined to be pathogenic (PMID: 23829769, 24462369). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002244861	SCV002512423	pathogenic	Leigh syndrome; Charcot-Marie-Tooth disease type 4K	2021-05-10	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PS4 supporting, PM2 moderate, PM3
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	RCV001849366	SCV004037153	pathogenic	Mitochondrial complex IV deficiency, nuclear type 1		criteria provided, single submitter	not provided
Neuberg Centre For Genomic Medicine, NCGM	RCV001849366	SCV004175829	pathogenic	Mitochondrial complex IV deficiency, nuclear type 1	2023-02-14	criteria provided, single submitter	clinical testing	The frameshift c.758_759del(p.Thr253SerfsTer38) variant has been reported previously in compound heterozygous state in an individual affected with Mitochondrial disorders (Invernizzi F, et. al., 2012). The variant is reported with an allele frequency of 0.001% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). This variant causes a frameshift starting with codon Threonine 253, changes this amino acid to Serine residue, and creates a premature Stop codon at position 38 of the new reading frame, denoted p.Thr253SerfsTer38. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV005208136	SCV005849303	pathogenic	Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2		criteria provided, single submitter	clinical testing	The frameshift c.758_759del(p.Thr253SerfsTer38) variant has been reported previously in compound heterozygous state in an individual(s) affected with Mitochondrial disorders (Invernizzi F, et. al., 2012). The p.Thr253SerfsTer38 variant is present with an allele frequency of 0.001% in the gnomAD exomes. This variant has been submitted to the ClinVar database as Pathogenic (multiple submissions). This variant causes a frameshift starting with codon Threonine 253, changes this amino acid to Serine residue, and creates a premature Stop codon at position 38 of the new reading frame, denoted p.Thr253SerfsTer38. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.