SDHA c.840C>T, p.Ile280=
NM_004168.4:c.840C>T
Likely Benign
This legacy system is being phased out as Project HERA V3 is rolled out.
ACMG/AMP Criteria Applied
PM2
BP4
BP6
BP7
Genetic Information
Gene & Transcript Details
Gene
SDHA
Transcript
NM_004168.4
MANE Select
Total Exons
15
Strand
Forward (+)
Reference Sequence
NC_000005.9
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_004168.1 | Alternative | 15 exons | Forward |
| NM_004168.2 | Alternative | 15 exons | Forward |
| NM_004168.3 | Alternative | 15 exons | Forward |
Variant Details
HGVS Notation
NM_004168.4:c.840C>T
Protein Change
I280=
Location
Exon 7
(Exon 7 of 15)
5'Exon Structure (15 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_004168.4
Genome Browser
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HGVS InputNM_004168:c.840C>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Likely Benign
Based on 2 submitter reviews in ClinVar
Submitter Breakdown
2 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Likely benign (2 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 0.84
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PVS1 rule states: "Null variant in a gene where loss of function (LoF) is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion in a LoF gene)". The evidence for this variant shows that it is a synonymous (I280=) change and does not introduce a premature stop codon or affect canonical splice sites. Therefore, PVS1 is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PS1 rule states: "Same amino acid change as a known pathogenic variant but different nucleotide change". The evidence for this variant shows no change to the amino acid sequence (I280=), so PS1 is not applicable.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PS2 rule states: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history". No de novo data are available for this variant. Therefore, PS2 is not applied.
PS3
PS3 (Not Applied) Strength Modified
PTEN Pre-processing rules are not applicable because this variant is in SDHA, not PTEN. According to standard ACMG guidelines, the PS3 rule states: "Well-established functional studies supportive of a damaging effect on the gene or gene product". No functional studies have been performed for this variant. Therefore, PS3 is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PS4 rule states: "Prevalence in affected individuals significantly increased compared with controls". There are no case-control or case series data demonstrating enrichment of this variant in affected individuals. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PM1 rule states: "Located in a mutational hot spot or well-established functional domain without benign variation". This synonymous variant does not lie within a known functional domain or hotspot. Therefore, PM1 is not applied.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the PM2 rule states: "Absent from controls (or at extremely low frequency if recessive)". The evidence for this variant shows it is absent from population databases including gnomAD (MAF = 0%). Therefore, PM2 is applied at Moderate strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PM3 rule states: "Detected in trans with a pathogenic variant for recessive disorders". There is no evidence of this variant in trans with a pathogenic allele. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PM4 rule states: "Protein length changes due to in-frame deletions/insertions or stop-loss variants". This variant is synonymous and does not alter protein length. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PM5 rule states: "Novel missense change at an amino acid residue where a different pathogenic missense change has been seen". This variant is synonymous, not missense. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PM6 rule states: "Assumed de novo, but without confirmation of paternity and maternity". No de novo data are available. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PP1 rule states: "Co-segregation with disease in multiple affected family members". No segregation data are available. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PP2 rule states: "Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease". This variant is synonymous, not missense. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PP3 rule states: "Multiple lines of computational evidence support a deleterious effect on the gene/gene product". Computational evidence (CADD 0.84, SpliceAI 0.04) suggests no deleterious effect; therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PP4 rule states: "Patient's phenotype or family history highly specific for a disease with a single genetic etiology". No phenotype data are provided. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PP5 rule states: "Reputable source reports variant as pathogenic, but without accessible evidence". The variant is reported as benign in ClinVar, not pathogenic. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BA1 rule states: "Allele frequency is too high for the disorder". The variant is absent from population databases, not at a high frequency. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BS1 rule states: "Allele frequency is greater than expected for the disorder". The variant is absent from population databases. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BS2 rule states: "Observed in healthy individuals with full penetrance expected at an early age". No such data are available. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BS3 rule states: "Well-established functional studies show no damaging effect on protein function or splicing". No functional studies exist. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BS4 rule states: "Lack of segregation in affected family members". No segregation analysis is available. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BP1 rule states: "Missense variant in a gene where only LoF causes disease". This variant is synonymous, not missense. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BP2 rule states: "Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant". No such data are available. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BP3 rule states: "In-frame deletions/insertions in a repetitive region without known function". This is not an in-frame indel. Therefore, BP3 is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the BP4 rule states: "Multiple lines of computational evidence suggest no impact on gene or gene product". Computational predictions (CADD score 0.84; SpliceAI 0.04) indicate no impact on protein function or splicing. Therefore, BP4 is applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BP5 rule states: "Variant found in a case with an alternate molecular basis for disease". No such case data are provided. Therefore, BP5 is not applied.
BP6
BP6 (Supporting)
According to standard ACMG guidelines, the BP6 rule states: "Reputable source reports variant as benign, but without accessible evidence". ClinVar reports this variant as Likely Benign by two laboratories without detailed evidence. Therefore, BP6 is applied at Supporting strength.
BP7
BP7 (Supporting)
According to standard ACMG guidelines, the BP7 rule states: "Synonymous variant with no predicted impact on splicing". This variant is synonymous (I280=) and SpliceAI predicts minimal splicing impact (score 0.04). Therefore, BP7 is applied at Supporting strength.