Variant: NM_000527.4(LDLR):c.1774G>A (p.Gly592Arg)

CA036598

373769 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: eeee2ff5-82c2-479e-abb7-3dbe70976e6b

Approved on: 2022-08-28

Published on: 2022-08-28

HGVS expressions

NM_000527.4:c.1774G>A
NM_000527.4(LDLR):c.1774G>A (p.Gly592Arg)
NC_000019.10:g.11116927G>A
CM000681.2:g.11116927G>A
NC_000019.9:g.11227603G>A
CM000681.1:g.11227603G>A
NC_000019.8:g.11088603G>A
NG_009060.1:g.32547G>A
ENST00000558518.6:c.1774G>A
ENST00000252444.9:n.2028G>A
ENST00000455727.6:c.1270G>A
ENST00000535915.5:c.1651G>A
ENST00000545707.5:c.1393G>A
ENST00000557933.5:c.1774G>A
ENST00000558013.5:c.1774G>A
ENST00000558518.5:c.1774G>A
ENST00000559340.1:n.426+715G>A
NM_001195798.1:c.1774G>A
NM_001195799.1:c.1651G>A
NM_001195800.1:c.1270G>A
NM_001195803.1:c.1393G>A
NM_000527.5:c.1774G>A
NM_001195798.2:c.1774G>A
NM_001195799.2:c.1651G>A
NM_001195800.2:c.1270G>A
NM_001195803.2:c.1393G>A
NM_000527.5(LDLR):c.1774G>A (p.Gly592Arg)

Likely Pathogenic

• Met criteria codes: PP4 PP3 PM2 PM5 PS4_Supporting

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

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.4(LDLR):c.1774G>A (p.Gly592Arg) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PM5, PP3, PS4_Supportign and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00009799 (0.0098%) in South Asian exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met. PM5 - 1 other missense variant in the same codon, NM_000527.5(LDLR):c.1775G>A (p.Gly592Glu) - classified as Pathogenic by the FH VCEP, so PM5 is met. PP3 - REVEL = 0.951. It is above 0.75, so PP3 is met. PS4_supporting - variant meets PM2 and was identified in 3 index cases with Dutch Lipid Clinic Scoring : Definite FH from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (Accession: SCV000583882.1 in ClinVar), so PS4_Supporting is met. PP4 - variant meets PM2 and was identified in 3 index cases with clinical FH criteria (please see PS4 for details), so PP4 is met.

Met criteria codes

• PP4: variant meets PM2 and was identified in 3 index cases with Dutch Lipid Clinic Scoring : Definite FH from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (Accession: SCV000583882.1 in ClinVar), so PP4 is met
• PP3: REVEL = 0.951. It is above 0.75, so PP3 is met
• PM2: PopMax MAF = 0.00009799 (0.0098%) in South Asian exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met
• PM5: 1 other missense variant in the same codon: - NM_000527.5(LDLR):c.1775G>A (p.Gly592Glu) - classified as Pathogenic by the FH VCEP so PM5 is met
• PS4_Supporting: variant meets PM2 and was identified in 3 index cases with Dutch Lipid Clinic Scoring : Definite FH from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (Accession: SCV000583882.1 in ClinVar), so PS4_Supporting is met

Not Met criteria codes

• PVS1: variant is missense and not in initiation codon, so not applicable
• PS2: no de novo occurrence
• PS3: There are no functional studies on this variant
• PS1: there is no missense variant that leads to the same amino acid change, so not met
• PP1: no segregation data
• PP2: not applicable
• PM6: no de novo occurrence
• PM3: not identified in cases with other variants
• 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
• BA1: FAF = 0.00002596 (0.003%) in South Asian exomes (gnomAD v2.1.1). It is not above 0.5%, so not met
• BS4: no segregation data
• BS3: There are no functional studies on this variant
• BS1: FAF = 0.00002596 (0.003%) in South Asian exomes (gnomAD v2.1.1). It is not above 0.5%, so not met
• BS2: variant was not tested in normolipidemic individuals, so not met
• BP5: not applicable
• BP7: variant is missense, so not applicable
• BP2: not identified in cases with other variants
• BP3: not applicable
• BP4: REVEL = 0.951. It is not below 0.50, so BP4 is not met
• BP1: not applicable