ClinVar Genomic variation as it relates to human health
NM_003002.4(SDHD):c.191_192del (p.Leu64fs)
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_003002.4(SDHD):c.191_192del (p.Leu64fs)
Variation ID: 6904 Accession: VCV000006904.11
- Type and length
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Microsatellite, 2 bp
- Location
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Cytogenetic: 11q23.1 11: 112088884-112088885 (GRCh38) [ NCBI UCSC ] 11: 111959608-111959609 (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 27, 2017 Feb 28, 2024 Jul 4, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003002.4:c.191_192del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002993.1:p.Leu64fs frameshift NM_001276503.2:c.169+911TC[2] intron variant NM_001276504.2:c.74_75del NP_001263433.1:p.Leu25fs frameshift NM_001276506.2:c.191_192del NP_001263435.1:p.Leu64fs frameshift NR_077060.2:n.222TC[2] non-coding transcript variant NC_000011.10:g.112088884TC[2] NC_000011.9:g.111959608TC[2] NG_012337.3:g.7038TC[2] NG_033145.1:g.2910GA[2] LRG_9:g.7038TC[2] LRG_9t1:c.191_192del LRG_9p1:p.Leu64fs - Protein change
- L64fs, L25fs
- Other names
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- Canonical SPDI
- NC_000011.10:112088883:TCTCTC:TCTC
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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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SDHD | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
631 | 767 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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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 (1) |
no assertion criteria provided
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Jul 1, 2001 | RCV000007313.13 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 25, 2016 | RCV000481193.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 17, 2018 | RCV001013655.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 4, 2022 | RCV002512870.9 |
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
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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
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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
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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
(Jul 25, 2016)
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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: SCV000568556.4
First in ClinVar: Apr 27, 2017 Last updated: Apr 27, 2017 |
Comment:
This deletion of two nucleotides in SDHD is denoted c.191_192delTC at the cDNA level and p.Leu64ProfsX4 (L64PfsX4) at the protein level. The normal sequence, with … (more)
This deletion of two nucleotides in SDHD is denoted c.191_192delTC at the cDNA level and p.Leu64ProfsX4 (L64PfsX4) at the protein level. The normal sequence, with the bases that are deleted in braces, is TCTC[TC]CACT. The deletion causes a frameshift which changes a Leucine to a Proline at codon 64, and creates a premature stop codon at position 4 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. SDHD c.191_192delTC tracked with disease in a large Australian family with hereditary paraganglioma (Badenhop 2001), and has been reported in multiple individuals with paraganglioma, including those with an apparently sporadic tumor (Burnichon 2009, Neumann 2009, Jafri 2013, Curras-Freixes 2015). We consider this variant to be pathogenic. (less)
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Pathogenic
(Oct 17, 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: SCV001174270.3
First in ClinVar: Mar 16, 2020 Last updated: Nov 29, 2022 |
Comment:
The c.191_192delTC variant, located in coding exon 3 of the SDHD gene, results from a deletion of two nucleotides at nucleotide positions 191 to 192, … (more)
The c.191_192delTC variant, located in coding exon 3 of the SDHD gene, results from a deletion of two nucleotides at nucleotide positions 191 to 192, causing a translational frameshift with a predicted alternate stop codon (p.L64Pfs*4). This alteration has been reported in individuals with familial paraganglioma (Badenhop RF et al. Genes Chromosomes Cancer. 2001 Jul;31:255-63; Badenhop RF et al. J. Med. Genet. 2004 Jul;41:e99; Cascón A et al. J. Clin. Endocrinol. Metab. 2009 May;94:1701-5). It has also been reported in individuals with apparently sporadic paraganglioma (Amar L et al. J. Clin. Oncol. 2005 Dec;23:8812-8; Currás-Freixes M et al. J. Med. Genet. 2015 Oct;52:647-56). Multiple cohort studies of patients with parangliomas have also identified this variant (Neumann HP et al. Cancer Res. 2009 Apr;69:3650-6; Burnichon N et al. J. Clin. Endocrinol. Metab. 2009 Aug;94:2817-27; Merlo A et al. J. Clin. Endocrinol. Metab. 2013 Oct;98:E1661-6; Jafri M et al. Clin. Endocrinol. (Oxf). 2013 Jun;78:898-906; de Cubas AA et al. Endocr. Relat. Cancer. 2013 Aug;20:477-93; Andrews KA et al. J. Med. Genet. 2018 Jun;55:384-394). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jul 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Carney-Stratakis syndrome
Paragangliomas with sensorineural hearing loss Pheochromocytoma Cowden syndrome 3
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000762653.3
First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 6904). This premature translational stop signal … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 6904). This premature translational stop signal has been observed in individual(s) with paraganglioma (PMID: 11391796, 15235042, 19454582, 23902947). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu64Profs*4) in the SDHD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SDHD are known to be pathogenic (PMID: 19454582, 19802898). (less)
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Pathogenic
(Jul 01, 2001)
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no assertion criteria provided
Method: literature only
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PARAGANGLIOMAS 1 WITH SENSORINEURAL HEARING LOSS
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000027510.4
First in ClinVar: Apr 04, 2013 Last updated: Jan 10, 2020 |
Comment on evidence:
In 1 of 2 unrelated families with familial carotid body paraganglioma associated with sensorineural hearing loss (see 168000) studied by Badenhop et al. (2001), they … (more)
In 1 of 2 unrelated families with familial carotid body paraganglioma associated with sensorineural hearing loss (see 168000) studied by Badenhop et al. (2001), they found a 2-bp deletion in exon 3 of the SDHD gene, creating a premature stop codon at position 67. They had information on 4 generations. One female with both paraganglioma and deafness/tinnitus had 5 children unaffected on both scores; another doubly affected female had 2 unaffected children and 1 child with deafness/tinnitus only. The latter finding was consistent with the fact that only affected males transmitted paraganglioma to their children and that monoallelic expression of the mutant (paternal) allele was observed, as expected for imprinting. (less)
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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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Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD. | Andrews KA | Journal of medical genetics | 2018 | PMID: 29386252 |
Recommendations for somatic and germline genetic testing of single pheochromocytoma and paraganglioma based on findings from a series of 329 patients. | Currás-Freixes M | Journal of medical genetics | 2015 | PMID: 26269449 |
Identification of somatic VHL gene mutations in sporadic head and neck paragangliomas in association with activation of the HIF-1α/miR-210 signaling pathway. | Merlo A | The Journal of clinical endocrinology and metabolism | 2013 | PMID: 23902947 |
Integrative analysis of miRNA and mRNA expression profiles in pheochromocytoma and paraganglioma identifies genotype-specific markers and potentially regulated pathways. | de Cubas AA | Endocrine-related cancer | 2013 | PMID: 23660872 |
Evaluation of SDHB, SDHD and VHL gene susceptibility testing in the assessment of individuals with non-syndromic phaeochromocytoma, paraganglioma and head and neck paraganglioma. | Jafri M | Clinical endocrinology | 2013 | PMID: 23072324 |
Tumor risks and genotype-phenotype-proteotype analysis in 358 patients with germline mutations in SDHB and SDHD. | Ricketts CJ | Human mutation | 2010 | PMID: 19802898 |
The succinate dehydrogenase genetic testing in a large prospective series of patients with paragangliomas. | Burnichon N | The Journal of clinical endocrinology and metabolism | 2009 | PMID: 19454582 |
Clinical predictors for germline mutations in head and neck paraganglioma patients: cost reduction strategy in genetic diagnostic process as fall-out. | Neumann HP | Cancer research | 2009 | PMID: 19351833 |
Genetics of pheochromocytoma and paraganglioma in Spanish patients. | Cascón A | The Journal of clinical endocrinology and metabolism | 2009 | PMID: 19258401 |
Genetic testing in pheochromocytoma or functional paraganglioma. | Amar L | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2005 | PMID: 16314641 |
The prevalence of SDHB, SDHC, and SDHD mutations in patients with head and neck paraganglioma and association of mutations with clinical features. | Badenhop RF | Journal of medical genetics | 2004 | PMID: 15235042 |
Novel mutations in the SDHD gene in pedigrees with familial carotid body paraganglioma and sensorineural hearing loss. | Badenhop RF | Genes, chromosomes & cancer | 2001 | PMID: 11391796 |
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Text-mined citations for rs387906358 ...
HelpRecord last updated Mar 23, 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.