FH c.648T>A, p.Asp216Glu
NM_000143.4:c.648T>A
Variant of Uncertain Significance (VUS)
The FH c.648T>A (p.D216E) variant is classified as a Variant of Uncertain Significance (VUS). It has moderate evidence of rarity (PM2) and computational benign support (BP4) supplemented by benign assertions (BP6), but lacks strong pathogenic or sufficient benign evidence. Additional functional, segregation, or case prevalence data are needed to resolve its significance.
ACMG/AMP Criteria Applied
PM2
BP4
BP6
Genetic Information
Gene & Transcript Details
Gene
FH
Transcript
NM_000143.4
MANE Select
Total Exons
10
Strand
Reverse (−)
Reference Sequence
NC_000001.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000143.2 | Alternative | 10 exons | Reverse |
| NM_000143.3 | RefSeq Select | 10 exons | Reverse |
Variant Details
HGVS Notation
NM_000143.4:c.648T>A
Protein Change
D216E
Location
Exon 5
(Exon 5 of 10)
5'Exon Structure (10 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 216 in gene FH
Variant interpretation based on transcript NM_000143.4
Genome Browser
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HGVS InputNM_000143:c.648T>A
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00778%
Rare
Highest in Population
European (non-Finnish)
0.0171%
Low Frequency
Global: 0.00778%
European (non-Finnish): 0.0171%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 282638Alt: 22Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00778%, 22/282638 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.0171%, 22/129022 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Uncertain Significance (VUS)
Based on 10 submitter reviews in ClinVar
Submitter Breakdown
4 VUS
5 LB
1 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Benign (1 clinical laboratories) and as Likely benign (5 clinical laboratories) and as Uncertain significance (4 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
No evidence of other pathogenic variants at position 216 in gene FH
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.512
0.512
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Pathogenic:
metasvm: Dmetalr: D
Benign:
CADD: 1.99polyphen_prediction: benignprimateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: "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: it is a missense change (D216E), not a null variant. Therefore, this criterion is not applied because the variant type does not meet the rule requirement.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a known pathogenic variant but different nucleotide change". The evidence for this variant shows: no previously established pathogenic variant at codon 216. Therefore, this criterion is not applied because there is no evidence of the same amino acid change reported as pathogenic.
PS2
PS2 (Not Applied) Strength Modified
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 de novo information available. Therefore, this criterion is not applied because de novo status has not been established.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: "Well-established functional studies supportive of a damaging effect on the gene or gene product". The evidence for this variant shows: no functional studies available. Therefore, this criterion is not applied because functional evidence is lacking.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "Prevalence in affected individuals significantly increased compared with controls". The evidence for this variant shows: no case-control or prevalence data. Therefore, this criterion is not applied because there is no evidence of increased prevalence in affected individuals.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot or well-established functional domain without benign variation". The evidence for this variant shows: no information on a mutational hotspot or critical functional domain at position 216. Therefore, this criterion is not applied because the variant is not known to reside in a hotspot or key domain.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive)". The evidence for this variant shows: present in gnomAD at MAF 0.00778%, extremely rare and absent homozygotes. Therefore, this criterion is applied at Moderate strength because the variant is observed at extremely low frequency in control populations.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant (for recessive disorders)". The evidence for this variant shows: no information on trans configuration with another variant. Therefore, this criterion is not applied because data on allele phase is missing.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions or stop-loss variants". The evidence for this variant shows: missense change with no alteration in protein length. Therefore, this criterion is not applied because the variant does not affect protein length.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different pathogenic missense change has been seen". The evidence for this variant shows: no reported pathogenic missense at codon 216. Therefore, this criterion is not applied because no other pathogenic variants at this residue have been described.
PM6
PM6 (Not Applied) Strength Modified
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 information on de novo status. Therefore, this criterion is not applied because de novo occurrence has not been assessed or assumed.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members". The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied because co-segregation evidence is unavailable.
PP2
PP2 (Not Applied) Strength Modified
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: both benign and pathogenic missense variants have been reported in FH; the rate of benign missense variation is not low. Therefore, this criterion is not applied because FH does not have a low rate of benign missense variation.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene/gene product (e.g., conservation, splicing impact)". The evidence for this variant shows: mixed in silico results and SpliceAI predicting no splicing impact. Therefore, this criterion is not applied because computational predictions are not consistently supportive of a deleterious effect.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient's phenotype or family history highly specific for a disease with a single genetic etiology". The evidence for this variant shows: no patient phenotype or family history provided. Therefore, this criterion is not applied because phenotypic specificity data is missing.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic, but without accessible evidence". The evidence for this variant shows: no reputable source reports pathogenicity; ClinVar entries do not list pathogenic. Therefore, this criterion is not applied because there are no pathogenic assertions.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is too high for the disorder (based on population data)". The evidence for this variant shows: MAF below 0.01 (0.00778%), far below threshold for BA1. Therefore, this criterion is not applied because the allele frequency is not above the BA1 threshold (>5%).
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for the disorder". The evidence for this variant shows: MAF low (<0.01%) and not greater than expected allele frequency. Therefore, this criterion is not applied because the frequency does not exceed the expected maximum.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: "Observed in healthy individuals with full penetrance expected at an early age". The evidence for this variant shows: presence in gnomAD likely includes healthy adults, but no clinical phenotyping to confirm no disease. Therefore, this criterion is not applied because unaffected status is not confirmed.
BS3
BS3 (Not Applied) Strength Modified
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 assays available. Therefore, this criterion is not applied because functional study data is absent.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected family members". The evidence for this variant shows: no segregation studies. Therefore, this criterion is not applied because segregation data is not available.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only LoF causes disease". The evidence for this variant shows: missense and LOF both documented in FH. Therefore, this criterion is not applied because missense variants can cause disease in FH.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant". The evidence for this variant shows: no allele phase information. Therefore, this criterion is not applied because trans or cis status is unknown.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without known function". The evidence for this variant shows: missense variant, no indel. Therefore, this criterion is not applied because BP3 is not relevant to missense changes.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact". The evidence for this variant shows: SpliceAI predicts no impact, CADD low, PolyPhen benign. Therefore, this criterion is applied at Supporting strength because computational evidence supports no impact.
BP5
BP5 (Not Applied) Strength Modified
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 case reports with alternative diagnosis. Therefore, this criterion is not applied because case context is lacking.
BP6
BP6 (Supporting)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign, but without accessible evidence". The evidence for this variant shows: multiple clinical labs in ClinVar report benign or likely benign without detailed evidence. Therefore, this criterion is applied at Supporting strength because there are benign assertions from reputable sources without accessible evidence.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted impact on splicing". The evidence for this variant shows: missense change, not synonymous. Therefore, this criterion is not applied because BP7 applies only to synonymous variants.