rs1131691065
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_003002.4(SDHD):c.314G>A(p.Trp105*) variant causes a stop gained, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_003002.4 stop_gained, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SDHD | NM_003002.4 | c.314G>A | p.Trp105* | stop_gained, splice_region_variant | 3/4 | ENST00000375549.8 | NP_002993.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SDHD | ENST00000375549.8 | c.314G>A | p.Trp105* | stop_gained, splice_region_variant | 3/4 | 1 | NM_003002.4 | ENSP00000364699.3 | ||
ENSG00000255292 | ENST00000532699.1 | n.314G>A | splice_region_variant, non_coding_transcript_exon_variant | 3/6 | 3 | ENSP00000456434.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461852Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727226
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Pheochromocytoma;C1847319:Carney-Stratakis syndrome;C1868633:Paragangliomas with sensorineural hearing loss;CN166604:Cowden syndrome 3 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 22, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the SDHD protein in which other variant(s) (p.Gln121*) have been determined to be pathogenic (PMID: 12000816; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 428939). This premature translational stop signal has been observed in individual(s) with paragangliomas (PMID: 23512077). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp105*) in the SDHD gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 55 amino acid(s) of the SDHD protein. - |
Mitochondrial complex 2 deficiency, nuclear type 3 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Jul 08, 2022 | PVS1 PM2 PS4_Supporting - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 01, 2024 | Nonsense variant predicted to result in protein truncation, as the last 55 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23512077, 32741965, 38815921) - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 14, 2019 | The p.W105* pathogenic mutation (also known as c.314G>A), located in coding exon 3 of the SDHD gene, results from a G to A substitution at nucleotide position 314. This changes the amino acid from a tryptophan to a stop codon within coding exon 3. This mutation was reported in a male diagnosed with two head/neck paragangliomas at age 20 and in a female diagnosed with one head/neck paraganglioma at age 13 (Fishbein L et al. Ann Surg Oncol. 2013 May;20(5):1444-50). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at