Variant: NM_000527.5(LDLR):c.1784G>T (p.Arg595Leu)

CA10585609

252029 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: 2237748f-a124-413b-97a0-3a3e93660c25

Approved on: 2022-02-01

Published on: 2022-07-11

HGVS expressions

NM_000527.5:c.1784G>T
NM_000527.5(LDLR):c.1784G>T (p.Arg595Leu)
NC_000019.10:g.11116937G>T
CM000681.2:g.11116937G>T
NC_000019.9:g.11227613G>T
CM000681.1:g.11227613G>T
NC_000019.8:g.11088613G>T
NG_009060.1:g.32557G>T
ENST00000558518.6:c.1784G>T
ENST00000252444.9:n.2038G>T
ENST00000455727.6:c.1280G>T
ENST00000535915.5:c.1661G>T
ENST00000545707.5:c.1403G>T
ENST00000557933.5:c.1784G>T
ENST00000558013.5:c.1784G>T
ENST00000558518.5:c.1784G>T
ENST00000559340.1:n.426+725G>T
NM_000527.4:c.1784G>T
NM_001195798.1:c.1784G>T
NM_001195799.1:c.1661G>T
NM_001195800.1:c.1280G>T
NM_001195803.1:c.1403G>T
NM_001195798.2:c.1784G>T
NM_001195799.2:c.1661G>T
NM_001195800.2:c.1280G>T
NM_001195803.2:c.1403G>T

Likely Pathogenic

• Met criteria codes: PM2 PP3 PM5_Strong

• Not Met criteria codes: PM3 PM1 PM4 PM6 PVS1 BS2 BS4 BS3 BS1 BP7 BP2 BP4 PS2 PS4 PS3 PS1 PP4 PP1 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.1784G>T (p.Arg595Leu) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PM5_strong) 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 = 0.959. It is above 0.75, so PP3 is Met. PM5_strong - 2 other missense variants in the same codon: - NM_000527.5(LDLR):c.1783C>T (p.Arg595Trp) (ClinVar ID: 161290) - Pathogenic by these guidelines - NM_000527.5(LDLR):c.1784G>A (p.Arg595Gln) (ClinVar ID: 183126) - Pathogenic by these guidelines There are 2 variants in the same codon classified as Pathogenic by these guidelines, so PM5_Strong is Met.

Met criteria codes

• PM2: This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met.
• PP3: REVEL = 0.959. It is above 0.75, so PP3 is Met.
• PM5_Strong: 2 other missense variants in the same codon: - NM_000527.5(LDLR):c.1783C>T (p.Arg595Trp) (ClinVar ID: 161290) - Pathogenic by these guidelines - NM_000527.5(LDLR):c.1784G>A (p.Arg595Gln) (ClinVar ID: 183126) - Pathogenic by these guidelines There are 2 variants in the same codon classified as Pathogenic by these guidelines, so PM5_Strong is Met.

Not Met criteria codes

• PM3: Not observed in trans with other LP/P variants, so PM3 is Not Met.
• PM1: Variant meets PM2 but is not located in exon 4 or alters a cysteine residues, so PM1 is Not Met.
• PM4: Variant meets PM2 and is missense, so PM4 is Not Met.
• PM6: de novo occurrence data not reported, so PM6 is Not Met.
• PVS1: Variant is missense, so PVS1 is Not Met.
• BS2: Case-control data not reported, so BS2 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: No population data was found for this variant in gnomAD (gnomAD v2.1.1), so BS1 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 = 0.959. It is not below 0.50, so BP4 is Not Met.
• PS2: de novo occurrence data not reported, so PS2 is Not Met.
• PS4: Variant meets PM2, but data reported does not meet any validated criteria, so PS4 is Not Met.
• PS3: There are no functional studies reported for this variant, so PS3 is not met.
• PS1: No more missense variants that lead to the same amino acid change, so PS1 is Not Met.
• PP4: Variant meets PM2, but data reported does not meet any validated criteria, so PP4 is Not Met.
• PP1: Segregation data not reported, so PP1 is Not Met.
• BA1: No population data was found for this variant in gnomAD (gnomAD v2.1.1), so BA1 is Not Met.