Variant summary: SURF1 c.532_535delAATA (p.Asn178GlufsX9) 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 was absent in 248160 control chromosomes. c.532_535delAATA has been reported in the literature in individuals affected with Leigh Syndrome and complex IV/cytochrome c oxidase deficiency (example, Bruno_2002, Kothari_2014, Lim_2014, Li_2018). These data indicate that the variant is likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation 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.532_535del (p.Asn178fs)
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.
(6)
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
6
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.532_535del (p.Asn178fs)
Variation ID: 372719 Accession: VCV000372719.10
- Type and length
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Deletion, 4 bp
- Location
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Cytogenetic: 9q34.2 9: 133352747-133352750 (GRCh38) [ NCBI UCSC ] 9: 136219602-136219605 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Jan 9, 2017 Jul 15, 2024 Jan 12, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_003172.4:c.532_535del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003163.1:p.Asn178fs frameshift NM_001280787.1:c.205_208del NP_001267716.1:p.Asn69fs frameshift NM_003172.2:c.532_535delAATA NM_003172.3:c.532_535delAATA NC_000009.12:g.133352749_133352752del NC_000009.11:g.136219604_136219607del NG_008477.1:g.8757_8760del - Protein change
- N69fs, N178fs
- Other names
- -
- Canonical SPDI
- NC_000009.12:133352746:TATTTA:TA
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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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
|
Oct 23, 2019 | RCV000414638.6 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 12, 2024 | RCV001290556.4 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 1, 2023 | RCV003447527.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
- | RCV004584703.1 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(Jan 18, 2021)
|
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: SCV001478628.1
First in ClinVar: Feb 12, 2021 Last updated: Feb 12, 2021 |
Comment:
Variant summary: SURF1 c.532_535delAATA (p.Asn178GlufsX9) 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.532_535delAATA (p.Asn178GlufsX9) 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 was absent in 248160 control chromosomes. c.532_535delAATA has been reported in the literature in individuals affected with Leigh Syndrome and complex IV/cytochrome c oxidase deficiency (example, Bruno_2002, Kothari_2014, Lim_2014, Li_2018). These data indicate that the variant is likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Oct 23, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000491136.3
First in ClinVar: Jan 09, 2017 Last updated: Jan 09, 2017 |
Comment:
Published in combination with other SURF1 variants in several individuals with symptoms of Leigh syndrome (Bruno et al., 2002; Sonam et al., 2014; Menezes et … (more)
Published in combination with other SURF1 variants in several individuals with symptoms of Leigh syndrome (Bruno et al., 2002; Sonam et al., 2014; Menezes et al., 2016); Not observed in large population cohorts (Lek et al., 2016); 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; This variant is associated with the following publications: (PMID: 26762927, 24262866, 24462369, 27475922, 12026244, 32445240) (less)
|
|
|
Pathogenic
(Mar 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Charcot-Marie-Tooth disease type 4K
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004175761.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Comment:
The frameshift c.532_535del(p.Asn178GlufsTer9) variant in SURF1 gene has been observed in individual(s) with SURF1 gene related disorders (Sonam et. al., 2014; Bruno et. al., 2002). … (more)
The frameshift c.532_535del(p.Asn178GlufsTer9) variant in SURF1 gene has been observed in individual(s) with SURF1 gene related disorders (Sonam et. al., 2014; Bruno et. al., 2002). This variant is also known as 531_534delAAAT and c531-533del (4 bp deletion at position 4547). The p.Asn178GlufsTer9 variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic by multiple submitters. This variant causes a frameshift starting with codon Asparagine 178, changes this amino acid to Glutamic Acid residue, and creates a premature Stop codon at position 9 of the new reading frame, denoted p.Asn178GlufsTer9. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SURF1 are known to be pathogenic (Echaniz-Laguna A et. al., 2013). For these reasons, this variant has been classified as Pathogenic. (less)
|
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Pathogenic
(Jul 26, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002018896.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
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Pathogenic
(Jan 12, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Leigh syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003441469.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Asn178Glufs*9) 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.Asn178Glufs*9) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Leigh syndrome (PMID: 12026244, 24262866, 32445240). This variant is also known as 531_534delAAAT and c531-533del (4 bp deletion at position 4547). ClinVar contains an entry for this variant (Variation ID: 372719). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial complex IV deficiency, nuclear type 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV005073952.1
First in ClinVar: Jul 15, 2024 Last updated: Jul 15, 2024 |
Comment:
The frameshift c.532_535del(p.Asn178GlufsTer9) variant in the SURF1 gene has been reported previously in individual(s) AFFECTED with Leigh syndrome (Sonam et. al., 2014; Bruno et. al., … (more)
The frameshift c.532_535del(p.Asn178GlufsTer9) variant in the SURF1 gene has been reported previously in individual(s) AFFECTED with Leigh syndrome (Sonam et. al., 2014; Bruno et. al., 2002). This variant is also known as 531_534delAAAT and c531-533del (4 bp deletion at position 4547). The p.Asn178GlufsTer9 variant is absent in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic by multiple submitters. This variant causes a frameshift starting with codon Asparagine 178, changes this amino acid to Glutamic Acid residue, and creates a premature Stop codon at position 9 of the new reading frame. This variant is predicted to cause a loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
|
Comment:
Comment:
Published in combination with other SURF1 variants in several individuals with symptoms of Leigh syndrome (Bruno et al., 2002; Sonam et al., 2014; Menezes et al., 2016); Not observed in large population cohorts (Lek et al., 2016); 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; This variant is associated with the following publications: (PMID: 26762927, 24262866, 24462369, 27475922, 12026244, 32445240)
Comment:
The frameshift c.532_535del(p.Asn178GlufsTer9) variant in SURF1 gene has been observed in individual(s) with SURF1 gene related disorders (Sonam et. al., 2014; Bruno et. al., 2002). This variant is also known as 531_534delAAAT and c531-533del (4 bp deletion at position 4547). The p.Asn178GlufsTer9 variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic by multiple submitters. This variant causes a frameshift starting with codon Asparagine 178, changes this amino acid to Glutamic Acid residue, and creates a premature Stop codon at position 9 of the new reading frame, denoted p.Asn178GlufsTer9. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SURF1 are known to be pathogenic (Echaniz-Laguna A et. al., 2013). For these reasons, this variant has been classified as Pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Asn178Glufs*9) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Leigh syndrome (PMID: 12026244, 24262866, 32445240). This variant is also known as 531_534delAAAT and c531-533del (4 bp deletion at position 4547). ClinVar contains an entry for this variant (Variation ID: 372719). For these reasons, this variant has been classified as Pathogenic.
Comment:
The frameshift c.532_535del(p.Asn178GlufsTer9) variant in the SURF1 gene has been reported previously in individual(s) AFFECTED with Leigh syndrome (Sonam et. al., 2014; Bruno et. al., 2002). This variant is also known as 531_534delAAAT and c531-533del (4 bp deletion at position 4547). The p.Asn178GlufsTer9 variant is absent in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic by multiple submitters. This variant causes a frameshift starting with codon Asparagine 178, changes this amino acid to Glutamic Acid residue, and creates a premature Stop codon at position 9 of the new reading frame. This variant is predicted to cause a loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
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.532_535delAATA (p.Asn178GlufsX9) 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 was absent in 248160 control chromosomes. c.532_535delAATA has been reported in the literature in individuals affected with Leigh Syndrome and complex IV/cytochrome c oxidase deficiency (example, Bruno_2002, Kothari_2014, Lim_2014, Li_2018). These data indicate that the variant is likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Published in combination with other SURF1 variants in several individuals with symptoms of Leigh syndrome (Bruno et al., 2002; Sonam et al., 2014; Menezes et al., 2016); Not observed in large population cohorts (Lek et al., 2016); 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; This variant is associated with the following publications: (PMID: 26762927, 24262866, 24462369, 27475922, 12026244, 32445240)
Comment:
The frameshift c.532_535del(p.Asn178GlufsTer9) variant in SURF1 gene has been observed in individual(s) with SURF1 gene related disorders (Sonam et. al., 2014; Bruno et. al., 2002). This variant is also known as 531_534delAAAT and c531-533del (4 bp deletion at position 4547). The p.Asn178GlufsTer9 variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic by multiple submitters. This variant causes a frameshift starting with codon Asparagine 178, changes this amino acid to Glutamic Acid residue, and creates a premature Stop codon at position 9 of the new reading frame, denoted p.Asn178GlufsTer9. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SURF1 are known to be pathogenic (Echaniz-Laguna A et. al., 2013). For these reasons, this variant has been classified as Pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Asn178Glufs*9) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Leigh syndrome (PMID: 12026244, 24262866, 32445240). This variant is also known as 531_534delAAAT and c531-533del (4 bp deletion at position 4547). ClinVar contains an entry for this variant (Variation ID: 372719). For these reasons, this variant has been classified as Pathogenic.
Comment:
The frameshift c.532_535del(p.Asn178GlufsTer9) variant in the SURF1 gene has been reported previously in individual(s) AFFECTED with Leigh syndrome (Sonam et. al., 2014; Bruno et. al., 2002). This variant is also known as 531_534delAAAT and c531-533del (4 bp deletion at position 4547). The p.Asn178GlufsTer9 variant is absent in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic by multiple submitters. This variant causes a frameshift starting with codon Asparagine 178, changes this amino acid to Glutamic Acid residue, and creates a premature Stop codon at position 9 of the new reading frame. This variant is predicted to cause a loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Pediatric Leigh Syndrome: Neuroimaging Features and Genetic Correlations. | Alves CAPF | Annals of neurology | 2020 | PMID: 32445240 |
| SURF1 mutations in Chinese patients with Leigh syndrome: Novel mutations, mutation spectrum, and the functional consequences. | Li Y | Gene | 2018 | PMID: 29933018 |
| A founder mutation in PET100 causes isolated complex IV deficiency in Lebanese individuals with Leigh syndrome. | Lim SC | American journal of human genetics | 2014 | PMID: 24462369 |
| Clinical and magnetic resonance imaging findings in patients with Leigh syndrome and SURF1 mutations. | Sonam K | Brain & development | 2014 | PMID: 24262866 |
| 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 |
| A novel mutation in the SURF1 gene in a child with Leigh disease, peripheral neuropathy, and cytochrome-c oxidase deficiency. | Bruno C | Journal of child neurology | 2002 | PMID: 12026244 |
| 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 rs1057517942 ...
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.