Variant: NM_000527.5(LDLR):c.139G>C (p.Asp47His)

CA404074850

440546 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: 67b39111-3008-4f7c-ad1e-56534ac6aeb8

Approved on: 2021-12-13

Published on: 2022-07-11

HGVS expressions

NM_000527.5:c.139G>C
NM_000527.5(LDLR):c.139G>C (p.Asp47His)
NC_000019.10:g.11100294G>C
CM000681.2:g.11100294G>C
NC_000019.9:g.11210970G>C
CM000681.1:g.11210970G>C
NC_000019.8:g.11071970G>C
NG_009060.1:g.15914G>C
ENST00000558518.6:c.139G>C
ENST00000252444.9:n.393G>C
ENST00000455727.6:c.139G>C
ENST00000535915.5:c.139G>C
ENST00000545707.5:c.139G>C
ENST00000557933.5:c.139G>C
ENST00000557958.1:n.225G>C
ENST00000558013.5:c.139G>C
ENST00000558518.5:c.139G>C
ENST00000560502.5:n.225G>C
NM_000527.4:c.139G>C
NM_001195798.1:c.139G>C
NM_001195799.1:c.139G>C
NM_001195800.1:c.139G>C
NM_001195803.1:c.139G>C
NM_001195798.2:c.139G>C
NM_001195799.2:c.139G>C
NM_001195800.2:c.139G>C
NM_001195803.2:c.139G>C

Uncertain Significance

• Met criteria codes: PM2 PP3

• Not Met criteria codes: PM6 PM1 PM4 PM3 PM5 PVS1 BS2 BS4 BS3 BS1 BP7 BP5 BP3 BP2 BP4 BP1 PS2 PS4 PS3 PS1 PP4 PP1 PP2 BA1

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specification: ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.1

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.139G>C (p.Asp47His) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2 and PP3) 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: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1). PP3 - REVEL = 0.977. It is above 0.75, so met.

Met criteria codes

• PM2: This variant is absent from gnomAD (gnomAD v2.1.1).
• PP3: REVEL = 0.977. It is above 0.75, so met.

Not Met criteria codes

• PM6: there is no case data available for this variant
• PM1: variant is missense and meets PM2, but it is not in exon 4 and does not alter Cys, so not met
• PM4: variant is missense, so not applicable
• PM3: there is no case data available for this variant
• PM5: 2 other missense variants in the same codon: - NM_000527.5(LDLR):c.139G>T (p.Asp47Tyr) - VUS by these guidelines - NM_000527.5(LDLR):c.139G>A (p.Asp47Asn) - VUS by expert panel on ClinVar so not met
• PVS1: variant is missense and not in initiation codon, so not applicable
• BS2: there is no case data available for this variant
• BS4: there is no case data available for this variant
• BS3: variant was not studied in functional studies, so not met
• BS1: This variant is absent from gnomAD (gnomAD v2.1.1).
• BP7: variant is missense, so not applicable
• BP5: not applicable
• BP3: not applicable
• BP2: there is no case data available for this variant
• BP4: REVEL = 0.977. It is not below 0.50, so not met
• BP1: not applicable
• PS2: there is no case data available for this variant
• PS4: there is no case data available for this variant
• PS3: variant was not studied in functional studies, so not met
• PS1: no other missense variant leads to the same amino acid change, so not met
• PP4: there is no case data available for this variant
• PP1: there is no case data available for this variant
• PP2: not applicable
• BA1: This variant is absent from gnomAD (gnomAD v2.1.1).