Variant: NM_000527.5(LDLR):c.1449G>C (p.Trp483Cys)

CA404086103

440646 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: 827b2b15-aab0-409f-b3c0-300fbf993884

Approved on: 2023-04-29

Published on: 2023-04-29

HGVS expressions

NM_000527.5:c.1449G>C
NM_000527.5(LDLR):c.1449G>C (p.Trp483Cys)
NC_000019.10:g.11113625G>C
CM000681.2:g.11113625G>C
NC_000019.9:g.11224301G>C
CM000681.1:g.11224301G>C
NC_000019.8:g.11085301G>C
NG_009060.1:g.29245G>C
ENST00000558518.6:c.1449G>C
ENST00000252444.9:n.1703G>C
ENST00000455727.6:c.945G>C
ENST00000535915.5:c.1326G>C
ENST00000545707.5:c.1068G>C
ENST00000557933.5:c.1449G>C
ENST00000558013.5:c.1449G>C
ENST00000558518.5:c.1449G>C
ENST00000559340.1:n.170G>C
NM_000527.4:c.1449G>C
NM_001195798.1:c.1449G>C
NM_001195799.1:c.1326G>C
NM_001195800.1:c.945G>C
NM_001195803.1:c.1068G>C
NM_001195798.2:c.1449G>C
NM_001195799.2:c.1326G>C
NM_001195800.2:c.945G>C
NM_001195803.2:c.1068G>C

Uncertain Significance

• Met criteria codes: PP3 PM2

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

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specification: ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.2

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.1449G>C (p.Trp483Cys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3) 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 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met. PP3 - REVEL = 0.951. It is above 0.75, so PP3 is Met.

Met criteria codes

• PP3: REVEL = 0.951. It is above 0.75, so PP3 is Met.
• PM2: This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met.

Not Met criteria codes

• PS1: 1 more missense variant that lead to the same amino acid change: - NM_000527.5(LDLR):c.1449G>T (p.Trp483Cys) (ClinVar ID 251850) - VUS by these guidelines --- variant is classified as VUS by these guidelines, so PS1 is not met.
• PS2: de novo occurrence data not reported, so PS2 is Not Met.
• PS3: There are no functional studies reported for this variant, so PS3 is not met.
• PS4: Variant meets PM2, but case data not reported, so PS4 is Not Met.
• BA1: This variant is absent from gnomAD (gnomAD v2.1.1), so BA1 is not met.
• PP1: Segregation data not reported, so PP1 is Not Met.
• PP4: Variant meets PM2, but case data not reported, so PP4 is Not Met.
• PM6: de novo occurrence data not reported, so PM6 is Not Met.
• PM1: Variant meets PM2 but is not located in exon 4 or alters a cysteine residues, so PM1 is Not Met.
• PM3: Not observed in trans with other LP/P variants, so PM3 is Not Met.
• PM4: Variant meets PM2 and is missense, so PM4 is Not Met.
• PM5: 3 other missense variants in the same codon: - NM_000527.5(LDLR):c.1449G>T (p.Trp483Cys) (ClinVar ID 251850) - VUS by these guidelines - NNM_000527.5(LDLR):c.1448G>T (p.Trp483Leu) (ClinVar ID 440645) - VUS by these guidelines - NM_000527.5(LDLR):c.1447T>C (p.Trp483Arg) (ClinVar ID 251847) - VUS by these guidelines There are no more variants in the same codon classified as Pathogenic by these guidelines, so PM5 is not met.
• BS4: Lack of segregation data not reported, so BS4 is Not Met.
• BS3: There are no functional studies reported for this variant, so BS3 is not met.
• BS1: This variant is absent from gnomAD (gnomAD v2.1.1), so BS1 is not met.
• BS2: No control individuals tested, so BS2 is Not Met.
• BP7: Variant is not synonymous, so BP7 is Not Met.
• BP2: Not observed in trans with other LP/P variants, so BP2 is Not Met.
• BP4: REVEL = 0.951. It is not below 0.50, so BP4 is Not Met.
• PVS1: Variant is missense, so PVS1 is Not Met.