ClinVar Genomic variation as it relates to human health
NM_017841.4(SDHAF2):c.232G>A (p.Gly78Arg)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_017841.4(SDHAF2):c.232G>A (p.Gly78Arg)
Variation ID: 401 Accession: VCV000000401.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q12.2 11: 61437820 (GRCh38) [ NCBI UCSC ] 11: 61205292 (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 Apr 4, 2013 Feb 14, 2024 Jan 4, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_017841.4:c.232G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_060311.1:p.Gly78Arg missense NC_000011.10:g.61437820G>A NC_000011.9:g.61205292G>A NG_023393.1:g.12696G>A LRG_519:g.12696G>A LRG_519t1:c.232G>A LRG_519p1:p.Gly78Arg Q9NX18:p.Gly78Arg - Protein change
- G78R
- Other names
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- Canonical SPDI
- NC_000011.10:61437819:G:A
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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SDHAF2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
552 | 568 |
Conditions - Germline
Condition
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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
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (3) |
criteria provided, single submitter
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Jan 4, 2023 | RCV000000428.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 8, 2018 | RCV000165971.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 13, 2020 | RCV000519058.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 20, 2020 | RCV000639339.9 |
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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Pathogenic
(Oct 13, 2020)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000617571.2
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
Comment:
Founder pathogenic variant in the Dutch population (Hensen 2012); Published functional studies demonstrate a damaging effect: variant results in a destabilized SDHAF2 protein and impairs … (more)
Founder pathogenic variant in the Dutch population (Hensen 2012); Published functional studies demonstrate a damaging effect: variant results in a destabilized SDHAF2 protein and impairs SDHAF2-SDHA interaction (Hao 2009, Bezawork-Gelata 2014); Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20972721, 19628817, 6286462, 28099933, 30050099, 24414418, 27587393, 22904323, 26627475, 23062074, 20071235, 21348866, 21224366, 25720320, 20938758, 23154507, 21082267, 21547462, 28384794, 20304625, 24739310, 31212687) (less)
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Pathogenic
(Feb 08, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000216728.6
First in ClinVar: Mar 24, 2015 Last updated: Nov 29, 2022 |
Comment:
The p.G78R pathogenic mutation (also known as c.232G>A), located in coding exon 2 of the SDHAF2 gene, results from a G to A substitution at … (more)
The p.G78R pathogenic mutation (also known as c.232G>A), located in coding exon 2 of the SDHAF2 gene, results from a G to A substitution at nucleotide position 232. The glycine at codon 78 is replaced by arginine, an amino acid with dissimilar properties. This mutation is considered a Dutch founder mutation and has been identified in multiple families with hereditary head and neck paragangliomas (HNPGL) (Hensen, EF et al. Clin Genet. 2012 Mar;81(3):284-8; Hao, HX et al. Science. 2009 Aug 28;325(5944):1139-42; Hoekstra AS et al. Oncotarget, 2017 Feb;8:14525-14536). In addition, this mutation co-segregated with disease in a Spanish family with HNPGL (Bayley, JP et al. Lancet Oncol. 2010 Apr;11(4):366-72) and was also observed in an apparently sporadic case of HNPGL in a patient with a right tympanic PGL (Piccini, V et al. Endocr Relat Cancer. 2012 Apr 10;19(2):149-55). Functional studies suggest that this mutation leads to a significant loss of flavination of SDHA, loss of activity of the succinate dehydrogenase complex, and reduced stability of SDHAF2 (Hao, HX et al. Science. 2009 Aug 28;325(5944):1139-42; Bezawork-Geleta A et al. FASEB J., 2014 Apr;28:1794-804). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jan 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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Paragangliomas 2
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004202956.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Sep 20, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hereditary pheochromocytoma-paraganglioma
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000760911.7
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine with arginine at codon 78 of the SDHAF2 protein (p.Gly78Arg). The glycine residue is highly conserved and there is a … (more)
This sequence change replaces glycine with arginine at codon 78 of the SDHAF2 protein (p.Gly78Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with paraganglioma in multiple families, and is considered a founder mutation in the Dutch population (PMID: 19628817, 21224366, 6286462, 6264239, 21348866). This variant was also observed in an individual with paraganglioma (PMID: 22241717) and a Spanish family, segregating with paraganglioma (PMID: 20071235). The studies have shown a parent-of-origin inheritance pattern (paternal transmission) in these families (PMID: 19628817, 21224366, 20071235, 28099933), but the clinical significance of this is not established yet. ClinVar contains an entry for this variant (Variation ID: 401). Experimental studies have shown that this missense change impairs interaction with SDHA, reduces protein stability, and decreases SDHA flavination (PMID: 19628817, 24414418). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 01, 2012)
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no assertion criteria provided
Method: literature only
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PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 2
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000020576.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 21, 2023 |
Comment on evidence:
In a large Dutch family, originally described by van Baars et al. (1982), segregating autosomal dominant paraganglioma (PPGL2; 601650), Hao et al. (2009) identified a … (more)
In a large Dutch family, originally described by van Baars et al. (1982), segregating autosomal dominant paraganglioma (PPGL2; 601650), Hao et al. (2009) identified a G-to-A transition at nucleotide 232 of exon 2 of the SDHAF2 gene, resulting in a gly-to-arg substitution at codon 78 (G78R). This mutation was not found in 400 unaffected control individuals and segregated with the phenotype in the family. Thirty-three individuals with the mutation had developed the disease, but not 7 individuals (median age 74 years) who had inherited the mutation from their mothers. This suggested an SDHD (602690)-like parent of origin-specific inheritance. Only 5 individuals (median age 42 years) with a paternal mutation had not developed overt paraganglioma. This reduced penetrance was thought to relate to young age and/or presence of undetected tumors. Hao et al. (2009) found that flavination of SDHA (600857) was decreased by approximately 95% in tumors from 3 patients with the PGL2 G78R mutation in comparison with control tumors from 2 sporadic PGL patients or with cultured human embryonic kidney and hepatoma cells and mouse skeletal cells and liver tissue. Mitochondrial localization of SDH5 was not compromised by this mutation. However, SDH5-G78R dramatically impaired the interaction of SDH5 with SDHA and slightly decreased the level of SDH5 protein. Human SDH5 was able to complement the yeast Sdh5 deletion glycerol growth defect, but human SDH5 carrying the G78R mutant had no effect. Hensen et al. (2012) identified the Dutch founder G78R mutation in 46 cases from 4 Dutch families out of a larger cohort of 1,045 patients from 340 Dutch families with paraganglioma and pheochromocytoma. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Paragangliomas 2
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000054642.3
First in ClinVar: Apr 04, 2013 Last updated: Aug 05, 2023 |
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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 |
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Hereditary Paraganglioma-Pheochromocytoma Syndromes. | Adam MP | - | 2023 | PMID: 20301715 |
Loss of maternal chromosome 11 is a signature event in SDHAF2, SDHD, and VHL-related paragangliomas, but less significant in SDHB-related paragangliomas. | Hoekstra AS | Oncotarget | 2017 | PMID: 28099933 |
Mitochondrial matrix proteostasis is linked to hereditary paraganglioma: LON-mediated turnover of the human flavinylation factor SDH5 is regulated by its interaction with SDHA. | Bezawork-Geleta A | FASEB journal : official publication of the Federation of American Societies for Experimental Biology | 2014 | PMID: 24414418 |
Head and neck paragangliomas: genetic spectrum and clinical variability in 79 consecutive patients. | Piccini V | Endocrine-related cancer | 2012 | PMID: 22241717 |
High prevalence of founder mutations of the succinate dehydrogenase genes in the Netherlands. | Hensen EF | Clinical genetics | 2012 | PMID: 21348866 |
SDHAF2 (PGL2-SDH5) and hereditary head and neck paraganglioma. | Kunst HP | Clinical cancer research : an official journal of the American Association for Cancer Research | 2011 | PMID: 21224366 |
SDHAF2 mutations in familial and sporadic paraganglioma and phaeochromocytoma. | Bayley JP | The Lancet. Oncology | 2010 | PMID: 20071235 |
SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. | Hao HX | Science (New York, N.Y.) | 2009 | PMID: 19628817 |
Genetic aspects of nonchromaffin paraganglioma. | van Baars F | Human genetics | 1982 | PMID: 6286462 |
Familial non-chromaffinic paragangliomas (glomus tumors) : clinical aspects. | van Baars F | The Laryngoscope | 1981 | PMID: 6264239 |
Text-mined citations for rs113560320 ...
HelpRecord last updated Feb 20, 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.