rs587776648
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_003002.4(SDHD):c.337_340delGACT(p.Asp113MetfsTer21) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_003002.4 frameshift
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SDHD | NM_003002.4 | c.337_340delGACT | p.Asp113MetfsTer21 | frameshift_variant | Exon 4 of 4 | ENST00000375549.8 | NP_002993.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SDHD | ENST00000375549.8 | c.337_340delGACT | p.Asp113MetfsTer21 | frameshift_variant | Exon 4 of 4 | 1 | NM_003002.4 | ENSP00000364699.3 | ||
ENSG00000255292 | ENST00000532699.1 | n.314+5816_314+5819delGACT | intron_variant | Intron 3 of 5 | 3 | ENSP00000456434.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Paragangliomas 1 Pathogenic:2
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
- -
not provided Pathogenic:2
This deletion of four nucleotides in SDHD is denoted c.337_340delGACT at the cDNA level and p.Asp113MetfsX21 (D113MfsX21) at the protein level. The normal sequence, with the bases that are deleted in brackets, is TACT[delGACT]ATGT. The deletion causes a frameshift, which changes an Aspartic Acid to a Methionine at codon 113, and creates a premature stop codon at position 21 of the new reading frame. This variant is predicted to cause loss of normal protein function through protein truncation as the last 47 amino acids are no longer translated. The disrupted region includes the helical transmembrane topological domain and the ubiquinone binding site (UniProt). This variant, also known as SDHD c.334_337delACTG, is a recurrent variant that has been reported in many individuals with early-onset and/or multiple paragangliomas/pheochromocytomas, and has been shown to track with disease in several families (Cascon 2002, Velasco 2005, Benn 2006, Lima 2007, Hermsen 2010, Lefebvre 2012). Paragangliomas from individuals carrying this variant have demonstrated loss of SDHB by IHC, and functional assays have shown that this variant results in a significant reduction of SDH enzyme activity and SDHB protein expression (Rapizzi 2012, Pai 2014). We consider this variant to be pathogenic. Of note, variants in the SDHD gene exhibit a parent-of-origin effect and, if shown to be pathogenic, typically cause symptoms only if inherited from the father. -
- -
Hereditary cancer-predisposing syndrome Pathogenic:2
The c.337_340delGACT pathogenic mutation, located in coding exon 4 of the SDHD gene, results from a deletion of 4 nucleotides at nucleotide positions 337 to 340, causing a translational frameshift with a predicted alternate stop codon (p.D113Mfs*21). This alteration occurs at the 3' terminus of theSDHD gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 29% of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This variant has been reported in multiple individuals diagnosed with paragangliomas and/or pheochromocytomas (Cascon A et al. Eur J Hum Genet, 2002 Aug;10:457-61; Neumann HP et al. JAMA, 2004 Aug;292:943-51; Amar L et al. J Clin Oncol, 2005 Dec;23:8812-8; Velasco A et al. Diagn Mol Pathol, 2005 Jun;14:109-14; Benn DE et al. J Clin Endocrinol Metab, 2006 Mar;91:827-36; Castellano M et al. Ann N Y Acad Sci, 2006 Aug;1073:156-65; Lima J et al. J Clin Endocrinol Metab, 2007 Dec;92:4853-64; Sevilla MA et al. Otolaryngol Head Neck Surg, 2009 May;140:724-9; Hermsen MA et al. Cell Oncol, 2010 Jan;32:275-83; Hensen EF et al. Clin Genet, 2012 Mar;81:284-8; Lefebvre S et al. Horm Metab Res, 2012 May;44:334-8; Pai R et al. APMIS, 2014 Nov;122:1130-5; Pandit R et al. Eur J Endocrinol, 2016 Oct;175:311-23). This variant is also referred to as SDHD 13732delGACT and SDHD c.334_337delACTG in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
PVS1_Strong, PS4_Strong, PP1_Strong, PM2_Supporting c.337_340del, located in exon 4 of the SDHD gene, consists in the deletion of 4 nucleotides, causing a translational frameshift with a predicted alternate stop codon (p.(Asp113Metfs*21)), losing 16% of the protein (>10%, PVS1_Strong). It is not present in the population database gnomAD v2.1.1, non cancer dataset (PM2_Supporting). The SpliceAI algorithm predicts no significant impact on splicing. his variant has been identified in several patients from different independent families cosegregating with clinical features of paraganglioma (PMID: 12111639, PMID: 15905695, PMID: 22517554, PMID: 17848412 among others and internal data)(PS4_Strong, PP1_Strong).In addition, multiple clinical databases (ClinVar (7x), LOVD(6x)) classified this variant as pathogenic. T Based on currently available information, the variant c.337_340del is classified as a pathogenic variant according to ACMG guidelines. -
Pheochromocytoma;C1847319:Carney-Stratakis syndrome;C1868633:Paragangliomas with sensorineural hearing loss;CN166604:Cowden syndrome 3 Pathogenic:1
This sequence change creates a premature translational stop signal (p.Asp113Metfs*21) in the SDHD gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 47 amino acid(s) of the SDHD protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with paragangliomas and/or pheochromocytomas (PMID: 12111639, 17848412, 21348866, 22517554, 27539324). It has also been observed to segregate with disease in related individuals. This variant is also known as 13732delGACT. ClinVar contains an entry for this variant (Variation ID: 6912). For these reasons, this variant has been classified as Pathogenic. -
Pheochromocytoma;C1847319:Carney-Stratakis syndrome;C3494181:Paragangliomas 1;C5436934:Mitochondrial complex 2 deficiency, nuclear type 3 Pathogenic:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at