ClinVar Genomic variation as it relates to human health
NM_003172.4(SURF1):c.563A>G (p.Asn188Ser)
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.
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.
Likely pathogenic(1); Uncertain significance(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_003172.4(SURF1):c.563A>G (p.Asn188Ser)
Variation ID: 215234 Accession: VCV000215234.9
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 9q34.2 9: 133352719 (GRCh38) [ NCBI UCSC ] 9: 136219574 (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 Oct 11, 2015 May 1, 2024 Oct 17, 2022 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_003172.4:c.563A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003163.1:p.Asn188Ser missense NM_001280787.1:c.236A>G NP_001267716.1:p.Asn79Ser missense NC_000009.12:g.133352719T>C NC_000009.11:g.136219574T>C NG_008477.1:g.8788A>G - Protein change
- N188S, N79S
- Other names
- -
- Canonical SPDI
- NC_000009.12:133352718:T:C
-
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.
Trans-Omics for Precision Medicine (TOPMed) 0.00008
The Genome Aggregation Database (gnomAD) 0.00010
The Genome Aggregation Database (gnomAD), exomes 0.00012
Exome Aggregation Consortium (ExAC) 0.00017
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023
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 |
637 | 731 |
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. |
---|---|---|---|---|
Likely pathogenic (2) |
criteria provided, single submitter
|
Oct 1, 2013 | RCV000196814.3 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Oct 17, 2022 | RCV001215689.4 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Mar 25, 2022 | RCV002222439.1 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Dec 14, 2021 | RCV002517263.2 |
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. |
|
---|---|---|---|---|---|
Likely pathogenic
(Oct 01, 2013)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000252351.10
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Comment:
p.Asn188Ser (AAT>AGT): c.563 A>G in exon 6 of the SURF1 gene (NM_003172.2) The c.563 A>G sequence change has not been published as a mutation, nor … (more)
p.Asn188Ser (AAT>AGT): c.563 A>G in exon 6 of the SURF1 gene (NM_003172.2) The c.563 A>G sequence change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. Multiple in-silico splice prediction models predict that c.563 A>G creates a cryptic donor site, which would be expected to lead to abnormal gene splicing. However, the true effect of c.563 A>G on splicing in vivo is not known. Therefore, based on the currently available information, it is unclear whether c.563 A>G is a disease-causing mutation or a rare benign variant. The variant is found in MITONUC-MITOP panel(s). (less)
|
|
Uncertain significance
(Oct 17, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Leigh syndrome
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV001387446.4
First in ClinVar: Jul 16, 2020 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 188 of the SURF1 protein (p.Asn188Ser). … (more)
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 188 of the SURF1 protein (p.Asn188Ser). This variant is present in population databases (rs200702528, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with SURF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 215234). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SURF1 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SURF1 function (PMID: 29933018). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
|
Uncertain significance
(Mar 25, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002500642.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Comment:
Variant summary: SURF1 c.563A>G (p.Asn188Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign … (more)
Variant summary: SURF1 c.563A>G (p.Asn188Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 249650 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in SURF1 causing Leigh Syndrome (0.00012 vs 0.0018), allowing no conclusion about variant significance. c.563A>G has been reported in the literature in a heterozygous individual affected with a suspected genetic disease (specific phenotype not provided) (Lazaridis_2016). This report does not provide unequivocal conclusions about association of the variant with Leigh Syndrome. Experimental evidence evaluating an impact on protein function showed that the variant decreases complex IV assembly without affecting SURF1 stability (Li_2018). This report does not allow convincing conclusions about the variant effect. A ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
|
|
Uncertain significance
(Dec 14, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV003697804.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
Li, 2018 Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001551334.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The SURF1 p.N188S variant was identified in dbSNP (ID: rs200702528) and ClinVar (classified as uncertain significance by Invitae and as likely pathogenic by GeneDx). The … (more)
The SURF1 p.N188S variant was identified in dbSNP (ID: rs200702528) and ClinVar (classified as uncertain significance by Invitae and as likely pathogenic by GeneDx). The variant was identified in control databases in 31 of 281050 chromosomes at a frequency of 0.0001103 (Genome Aggregation Database March 6, 2019, v2.1.1). The p.N188 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen- 2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. Functional analysis suggests that this variant does not affect protein expression, but has mild effects on complex IV assembly (Li_2018_PMID: 29933018). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome and Splice AI genome) do not predict an effect on splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
|
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. |
Citations for germline classification of this variant
HelpTitle | 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 |
Outcome of Whole Exome Sequencing for Diagnostic Odyssey Cases of an Individualized Medicine Clinic: The Mayo Clinic Experience. | Lazaridis KN | Mayo Clinic proceedings | 2016 | PMID: 26944241 |
Text-mined citations for rs200702528 ...
HelpRecord last updated May 19, 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.