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.
ClinVar Genomic variation as it relates to human health
NM_003172.4(SURF1):c.574_575insCTGC (p.Arg192fs)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(7)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_003172.4(SURF1):c.574_575insCTGC (p.Arg192fs)
Variation ID: 419973 Accession: VCV000419973.16
- Type and length
-
Insertion, 4 bp
- Location
-
Cytogenetic: 9q34.2 9: 133352707-133352708 (GRCh38) [ NCBI UCSC ] 9: 136219562-136219563 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 27, 2017 Jul 23, 2024 Jan 21, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_003172.4:c.574_575insCTGC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003163.1:p.Arg192fs frameshift NM_001280787.1:c.247_248insCTGC NP_001267716.1:p.Arg83fs frameshift NC_000009.12:g.133352708_133352709insCAGG NC_000009.11:g.136219563_136219564insCAGG NG_008477.1:g.8799_8800insCTGC - Protein change
- R192fs, R83fs
- Other names
- -
- Canonical SPDI
- NC_000009.12:133352707:G:GCAGG
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| SURF1 | - | - |
GRCh38 GRCh38 GRCh37 |
647 | 749 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
May 26, 2023 | RCV000478177.6 | |
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 21, 2024 | RCV001193160.5 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Feb 2, 2022 | RCV002272252.7 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Oct 11, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Leigh syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001361834.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
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 … (more)
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. (less)
|
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: research
|
Leigh syndrome
Affected status: unknown
Allele origin:
germline
|
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill
Study: CSER_NCGENES_2
Accession: SCV001423867.1 First in ClinVar: Jul 26, 2020 Last updated: Jul 26, 2020 |
Comment:
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 … (more)
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). (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Feb 17, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001714334.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Comment:
PVS1, PS4_moderate, PM2
Number of individuals with the variant: 1
|
|
|
Pathogenic
(May 26, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000568229.4
First in ClinVar: Apr 27, 2017 Last updated: Jun 10, 2023 |
Comment:
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 … (more)
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) (less)
|
|
|
Pathogenic
(Mar 04, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial complex IV deficiency, nuclear type 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
maternal
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV002764919.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Number of individuals with the variant: 1
Clinical Features:
Increased circulating lactate concentration (present) , Vomiting (present) , Symmetric lesions of the basal ganglia (present) , Hypotonia (present)
|
|
|
Pathogenic
(Jan 21, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Leigh syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003253282.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Feb 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial complex IV deficiency, nuclear type 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557718.2
First in ClinVar: Aug 08, 2022 Last updated: Jul 23, 2024 |
Comment:
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 … (more)
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 (less)
|
Comment:
Comment:
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).
Comment:
PVS1, PS4_moderate, PM2
Comment:
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)
Comment:
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.
Comment:
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
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
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.
Comment:
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).
Comment:
PVS1, PS4_moderate, PM2
Comment:
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)
Comment:
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.
Comment:
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
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| SURF1 mutations in Chinese patients with Leigh syndrome: Novel mutations, mutation spectrum, and the functional consequences. | Li Y | Gene | 2018 | PMID: 29933018 |
| Long survival in Leigh syndrome: new cases and review of literature. | Aulbert W | Neuropediatrics | 2014 | PMID: 25111564 |
| SURF1 deficiency causes demyelinating Charcot-Marie-Tooth disease. | Echaniz-Laguna A | Neurology | 2013 | PMID: 24027061 |
| SURF1-associated Leigh syndrome: a case series and novel mutations. | Lee IC | Human mutation | 2012 | PMID: 22488715 |
| Novel SURF1 mutation in a child with subacute encephalopathy and without the radiological features of Leigh Syndrome. | Salviati L | American journal of medical genetics. Part A | 2004 | PMID: 15214016 |
| Mutations in the SURF1 gene associated with Leigh syndrome and cytochrome C oxidase deficiency. | Péquignot MO | Human mutation | 2001 | PMID: 11317352 |
| Missense mutations in SURF1 associated with deficient cytochrome c oxidase assembly in Leigh syndrome patients. | Poyau A | Human genetics | 2000 | PMID: 10746561 |
| Loss-of-function mutations of SURF-1 are specifically associated with Leigh syndrome with cytochrome c oxidase deficiency. | Tiranti V | Annals of neurology | 1999 | PMID: 10443880 |
Text-mined citations for rs782289759 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.