Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_003000.3 | MANE Select | 1015 nt | 14–856 |
| NM_003000.1 | Alternative | 1100 nt | 135–977 |
| NM_003000.2 | RefSeq Select | 1161 nt | 152–994 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
OpenVariant summary: The SDHB c.170A>G (p.His57Arg) variant involves the alteration of a non-conserved nucleotide located in the Succinate dehydogenase/fumarate reductase N-terminal (IPR025192) and the 2Fe-2S ferredoxin-type iron-sulfur binding domains (IPR001041) (InterPro). 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 222/278486 control chromosomes (gnomAD and Bodian_2014) at a frequency of 0.0007972, which is approximately 911 times the estimated maximal expected allele frequency of a pathogenic SDHB variant (0.0000009), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. The variant of interest has not, to our knowledge, been reported in individuals with Hereditary paraganglioma-pheochromocytoma syndrome via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign.
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
"This variant has been reported in ClinVar as Likely benign (8 clinical laboratories) and as Benign (5 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | 500 bp |
| Donor Loss (DL) | 0.0 | -30 bp |
| Acceptor Gain (AG) | 0.0 | 97 bp |
| Donor Gain (DG) | 0.0 | 350 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to standard ACMG guidelines, the rule for PVS1 is: "Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon or multiexon deletion) in a gene where loss-of-function is a known mechanism of disease." The evidence for this variant shows: it is a missense change (p.H57R) and not predicted to cause loss-of-function. Therefore, this criterion is not applied at any strength because the variant is not a null variant.
PS1 (Not Applied)
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." The evidence for this variant shows: no previously established pathogenic variant results in the same p.H57R change. Therefore, PS1 is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." The evidence for this variant shows: no data on de novo occurrence. Therefore, PS2 is not applied.
PS3 (Not Applied)
According to standard ACMG guidelines, the rule for PS3 is: "Well-established functional studies show a deleterious effect on the gene or gene product." The evidence for this variant shows: no functional studies have been performed. Therefore, PS3 is not applied.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: "The prevalence of the variant in affected individuals is significantly increased compared with controls." The evidence for this variant shows: no case–control or prevalence data. Therefore, PS4 is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot and/or critical and well-established functional domain without benign variation." The evidence for this variant shows: no data indicating p.H57 is in a mutational hotspot or critical domain. Therefore, PM1 is not applied.
PM2 (Not Applied)
According to standard ACMG guidelines, the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or ExAC." The evidence for this variant shows: global MAF is 0.0824% but the maximum subpopulation MAF (African/African American) is 0.793%, which exceeds thresholds for extremely rare variants in an autosomal dominant disorder. Therefore, PM2 is not applied at moderate strength because the variant frequency is not sufficiently low when considering subpopulations.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: "For recessive disorders, detected in trans with a pathogenic variant." The evidence for this variant shows: SDHB disorders are autosomal dominant, and no in-trans observations are relevant. Therefore, PM3 is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions in non-repeat regions or stop-loss variants." The evidence for this variant shows: p.H57R is a missense change without length alteration. Therefore, PM4 is not applied.
PM5 (Not Applied)
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different missense change is pathogenic." The evidence for this variant shows: no other missense changes at codon 57 are known to be pathogenic. Therefore, PM5 is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity." The evidence for this variant shows: no de novo data. Therefore, PM6 is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 is: "Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease." The evidence for this variant shows: no segregation data. Therefore, PP1 is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease." The evidence for this variant shows: insufficient data on benign missense variation rate and disease mechanism specificity. Therefore, PP2 is not applied.
PP3 (Not Applied)
According to standard ACMG guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene or gene product." The evidence for this variant shows: computational predictions are mixed with a preponderance of benign calls, and SpliceAI predicts no splicing impact, supporting BP4 instead. Therefore, PP3 is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology." The evidence for this variant shows: no phenotype or family history data. Therefore, PP4 is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic, but evidence is not available for independent evaluation." The evidence for this variant shows: no reputable source reports it as pathogenic. Therefore, PP5 is not applied.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is >5% in general or appropriate subpopulation databases." The evidence for this variant shows: global and subpopulation MAFs are <5%. Therefore, BA1 is not applied.
BS1 (Strong)
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for disorder." The evidence for this variant shows: maximum subpopulation MAF is 0.793%, which is inconsistent with the rarity expected for an autosomal dominant disorder caused by SDHB variants. Therefore, BS1 is applied at Strong strength because the variant frequency exceeds the expected maximum for disease-causing alleles.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: "Observed in a healthy adult individual for a fully penetrant dominant gene/disorder." The evidence for this variant shows: no reports of observation in healthy controls with phenotype data. Therefore, BS2 is not applied.
BS3 (Not Applied)
According to standard ACMG guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect on protein function or splicing." The evidence for this variant shows: no functional studies available. Therefore, BS3 is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected members of a family." The evidence for this variant shows: no segregation data. Therefore, BS4 is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene for which primarily truncating variants are known to cause disease." The evidence for this variant shows: pathogenic missense variants are reported in SDHB. Therefore, BP1 is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for a fully penetrant dominant disorder." The evidence for this variant shows: no in-trans observations with pathogenic variants. Therefore, BP2 is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without a known function." The evidence for this variant shows: it is a missense substitution. Therefore, BP3 is not applied.
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact on gene or gene product." The evidence for this variant shows: SpliceAI predicts no splicing impact, and multiple in silico predictors (CADD, PolyPhen-2, MetaSVM, PrimateAI) indicate benign. Therefore, BP4 is applied at Supporting strength because computational evidence predominantly supports a benign effect.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows: no cases with alternate molecular diagnoses reported. Therefore, BP5 is not applied.
BP6 (Supporting)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source recently reports variant as benign, but evidence is not available to perform an independent evaluation." The evidence for this variant shows: ClinVar entries include Likely Benign (8 labs) and Benign (5 labs) with no primary evidence. Therefore, BP6 is applied at Supporting strength because a reputable database reports the variant as benign.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted impact on splicing and no conservation at nucleotide level." The evidence for this variant shows: it is a missense change. Therefore, BP7 is not applied.