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

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SDHD
NM_003002.4 stop_gained, splice_region

Scores

5
1
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 9.35
Variant links:
Genes affected
SDHD (HGNC:10683): (succinate dehydrogenase complex subunit D) This gene encodes a member of complex II of the respiratory chain, which is responsible for the oxidation of succinate. The encoded protein is one of two integral membrane proteins anchoring the complex to the matrix side of the mitochondrial inner membrane. Mutations in this gene are associated with the formation of tumors, including hereditary paraganglioma. Transmission of disease occurs almost exclusively through the paternal allele, suggesting that this locus may be maternally imprinted. There are pseudogenes for this gene on chromosomes 1, 2, 3, 7, and 18. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2013]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 16 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-112089011-G-A is Pathogenic according to our data. Variant chr11-112089011-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 428939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SDHDNM_003002.4 linkc.314G>A p.Trp105* stop_gained, splice_region_variant 3/4 ENST00000375549.8 NP_002993.1 O14521-1A0A0S2Z4J3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SDHDENST00000375549.8 linkc.314G>A p.Trp105* stop_gained, splice_region_variant 3/41 NM_003002.4 ENSP00000364699.3 O14521-1
ENSG00000255292ENST00000532699.1 linkn.314G>A splice_region_variant, non_coding_transcript_exon_variant 3/63 ENSP00000456434.1 H3BRW5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461852
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
727226
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Pheochromocytoma;C1847319:Carney-Stratakis syndrome;C1868633:Paragangliomas with sensorineural hearing loss;CN166604:Cowden syndrome 3 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 22, 2022For 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 submitterclinical testingGreenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic CenterJul 08, 2022PVS1 PM2 PS4_Supporting -
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxJul 01, 2024Nonsense 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 submitterclinical testingAmbry GeneticsFeb 14, 2019The 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.63
CADD
Pathogenic
48
DANN
Uncertain
0.98
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Pathogenic
0.99
D
Vest4
0.95
GERP RS
4.1

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.61
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.61
Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1131691065; hg19: chr11-111959735; API