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

CA041346

252360 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

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

Likely Benign

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Conflicting Evidence"

• Met criteria codes: BS3 PS4_Supporting BP4 PP4 PM2

• Not Met criteria codes: BS4 BS1 PVS1 BS2 BP7 BP5 BP3 BP2 BP1 PS2 PS3 PS1 BA1 PP1 PP3 PP2 PM6 PM4 PM3 PM1 PM5

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

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

• BS3: PMID: 25386756 - Level 1 assay - Expression >90%, uptake 90%, degradation of 125I-LDL 90%.
• 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.
• 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).
• PM2: PopMa MAF = 0.0001629 (0.01629%) in 'Other' (gnomAD v2.1.1). MAF is below 0.02%.

Not Met criteria codes

• 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%.
• PVS1: Missense variant. Not applicable.
• BS2: No family members tested.
• 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.
• BA1: FAF = 0.00001121 (0.001121%) in European non-Finnish exomes (gnomAD v2.1.1). FAF is not above 0.5%.
• 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.
• PM6: no de novo occurrence was identified
• 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.