Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • See Evidence submitted by expert panel for details.

Variant: NM_000527.5(LDLR):c.2575G>A (p.Val859Met)

CA041346

252360 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: b69dff69-840b-4103-bcdf-832247919271
Approved on: 2021-06-24
Published on: 2021-06-24

HGVS expressions

NM_000527.5:c.2575G>A
NM_000527.5(LDLR):c.2575G>A (p.Val859Met)
ENST00000558518.6:c.2575G>A
ENST00000252444.9:n.2829G>A
ENST00000455727.6:c.2071G>A
ENST00000535915.5:c.2452G>A
ENST00000545707.5:c.2041G>A
ENST00000557933.5:c.2637G>A
ENST00000558013.5:c.2569G>A
ENST00000558518.5:c.2575G>A
ENST00000560628.1:n.109-1787G>A
NM_000527.4:c.2575G>A
NM_001195798.1:c.2569G>A
NM_001195799.1:c.2452G>A
NM_001195800.1:c.2071G>A
NM_001195803.1:c.2041G>A
NM_001195798.2:c.2569G>A
NM_001195799.2:c.2452G>A
NM_001195800.2:c.2071G>A
NM_001195803.2:c.2041G>A
NC_000019.10:g.11131308G>A
CM000681.2:g.11131308G>A
NC_000019.9:g.11241984G>A
CM000681.1:g.11241984G>A
NC_000019.8:g.11102984G>A
NG_009060.1:g.46928G>A
More

Likely Benign

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Conflicting Evidence"
Met criteria codes 5
PM2 PS4_Supporting BS3 BP4 PP4
Not Met criteria codes 21
PM4 PM3 PM1 PM5 PM6 PVS1 BA1 BS2 BS4 BS1 BP7 BP5 BP3 BP2 BP1 PS2 PS3 PS1 PP1 PP3 PP2

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
NM_000527.5(LDLR):c.2575G>A (p.Val859Met) variant is classified as Likely benign for Familial Hypercholesterolemia by applying evidence codes (BS3, BP4, and PM2, PP4 and PS4_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: BS3 - PMID: 25386756 - Level 1 assay - Expression >90%, uptake 90%, degradation of 125I-LDL 90%. BP4 - REVEL: 0,209. Score is below 0,5. Splicing predictors - negative. so BP4 is met. PM2 - PopMa MAF = 0.0001629 (0.01629%) in 'Other' (gnomAD v2.1.1). PP4 - Variant meets PM2 and is identified in 2 unrelated index cases who fulfill Simon-Broome criteria for FH (Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge). PS4_supporting - Variant meets PM2 and is identified in 2 unrelated index cases from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge who fulfill Simon-Broome criteria for FH. Variant has 1 Strong and 1 Supporting evidence codes towards Benign, enough to classify as Likely benign, and only 1 Moderate and 1 Supporting evidence codes towards Pathogenic. The Benign criteria overwhelms the Pathogenic criteria, so we are confident in classifying this variant as Likely benign
Met criteria codes
PM2
PopMa MAF = 0.0001629 (0.01629%) in 'Other' (gnomAD v2.1.1). MAF is below 0.02%.
PS4_Supporting
Variant meets PM2 and is identified in 2 unrelated index cases from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge who fulfill Simon-Broome criteria for FH.
BS3
PMID: 25386756 - Level 1 assay - Expression >90%, uptake 90%, degradation of 125I-LDL 90%.
Expression >90%, uptake 90%, degradation of 125I-LDL 90% PubMed:25386756
BP4
REVEL: 0,209. Score is below 0,5. Splicing predictors - negative. so BP4 is met
PP4
Variant meets PM2 and is identified in 2 unrelated index cases who fulfill Simon-Broome criteria for FH (Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge).
Not Met criteria codes
PM4
Missense variant. Not applicable.
PM3
Not identified in individuals with other variants.
PM1
Missense at codon 859. PM2 is Met, but it is not exon 4 or any of the 60 Cys residues listed. Not applicable.
PM5
The current variant is the only variant found in this codon in ClinVar.
PM6
no de novo occurrence was identified
PVS1
Missense variant. Not applicable.
BA1
FAF = 0.00001121 (0.001121%) in European non-Finnish exomes (gnomAD v2.1.1). FAF is not above 0.5%.
BS2
No family members tested.
BS4
2 cases of non-segregations in 1 family were identified (Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge). At least 2 cases in at least 2 families are needed.
BS1
FAF = 0.00001121 (0.001121%) in European non-Finnish exomes (gnomAD v2.1.1). FAF is not above 0.2%.
BP7
Missense variant. Not applicable.
BP5
Not applicable.
BP3
Not applicable.
BP2
Not identified in individuals with other variants.
BP1
Not applicable.
PS2
no de novo occurrence was identified
PS3
PMID: 25386756 - Level 1 assay - Expression >90%, uptake 90%, degradation of 125I-LDL 90%. PS3 not met.
PS1
The current variant is the only variant found in this codon in ClinVar.
PP1
Variant segregates with phenotype in 1 informative meiosis in 1 family from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. Minimal number of meioses is 2.
PP3
REVEL: 0,209. Score is not above 0,75. Splicing predictors - negative.
PP2
Not applicable.
Curation History
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