rs782349178
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_003172.4(SURF1):c.758_759del(p.Thr253SerfsTer38) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000876 in 1,598,184 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T253T) has been classified as Likely benign.
Frequency
Consequence
NM_003172.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SURF1 | NM_003172.4 | c.758_759del | p.Thr253SerfsTer38 | frameshift_variant | 8/9 | ENST00000371974.8 | |
SURF1 | NM_001280787.1 | c.431_432del | p.Thr144SerfsTer38 | frameshift_variant | 7/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SURF1 | ENST00000371974.8 | c.758_759del | p.Thr253SerfsTer38 | frameshift_variant | 8/9 | 1 | NM_003172.4 | P1 | |
SURF1 | ENST00000615505.4 | c.431_432del | p.Thr144SerfsTer38 | frameshift_variant | 7/8 | 1 | |||
SURF1 | ENST00000437995.1 | n.668_669del | non_coding_transcript_exon_variant | 7/8 | 5 | ||||
SURF1 | ENST00000495952.5 | n.748_749del | non_coding_transcript_exon_variant | 4/5 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152210Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000135 AC: 3AN: 221410Hom.: 0 AF XY: 0.0000168 AC XY: 2AN XY: 119378
GnomAD4 exome AF: 0.00000692 AC: 10AN: 1445974Hom.: 0 AF XY: 0.00000557 AC XY: 4AN XY: 717730
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152210Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74354
ClinVar
Submissions by phenotype
Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | Feb 14, 2023 | 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. - |
Pathogenic, criteria provided, single submitter | not provided | Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | DASA | Mar 05, 2022 | 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. - |
Leigh syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 30, 2023 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 12, 2016 | 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. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 28, 2019 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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 (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 11317352, 23829769, 10443880, 16326995, 21611066, 22310368, 29933018) - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 31, 2021 | - - |
Leigh syndrome;C4225246:Charcot-Marie-Tooth disease type 4K Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | May 10, 2021 | ACMG classification criteria: PVS1 very strong, PS4 supporting, PM2 moderate, PM3 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at