Variant: NM_000527.5(LDLR):c.1951G>T (p.Asp651Tyr)

CA10585693

252127 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: f9cc13a9-0509-451a-a856-60c50af7c90d

Approved on: 2023-03-20

Published on: 2023-03-31

HGVS expressions

NM_000527.5:c.1951G>T
NM_000527.5(LDLR):c.1951G>T (p.Asp651Tyr)
NC_000019.10:g.11120197G>T
CM000681.2:g.11120197G>T
NC_000019.9:g.11230873G>T
CM000681.1:g.11230873G>T
NC_000019.8:g.11091873G>T
NG_009060.1:g.35817G>T
ENST00000252444.10:c.2209G>T
ENST00000559340.2:c.*20G>T
ENST00000560467.2:c.1831G>T
ENST00000558518.6:c.1951G>T
ENST00000252444.9:c.2205G>T
ENST00000455727.6:c.1447G>T
ENST00000535915.5:c.1828G>T
ENST00000545707.5:c.1570G>T
ENST00000557933.5:c.1951G>T
ENST00000558013.5:c.1951G>T
ENST00000558518.5:c.1951G>T
ENST00000559340.1:c.532G>T
NM_000527.4:c.1951G>T
NM_001195798.1:c.1951G>T
NM_001195799.1:c.1828G>T
NM_001195800.1:c.1447G>T
NM_001195803.1:c.1570G>T
NM_001195798.2:c.1951G>T
NM_001195799.2:c.1828G>T
NM_001195800.2:c.1447G>T
NM_001195803.2:c.1570G>T

Likely Pathogenic

• Met criteria codes: PM2 PS3 PP3 PP4

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

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.1951G>T (p.Asp651Tyr) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PS3, PM2, PP3, 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: PS3: Level 1 assays: PMID 32937241: Heterologous cells (CHO) - results - 53% LDLR expression, 50% binding, and 80% uptake. Expression and binding are below 70% of wild-type, so functional study is consistent with damaging effect. PS3 is met. PM2: This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met. PP3: REVEL = 0.933. It is above 0.75, so PP3 is met. PP4: Variant meet PM2. PMID: 16389549 (Humphries et al., 2005) - 1 case who fulfills Simon-Broome criteria for FH. So PP4 is met.

Met criteria codes

• PM2: This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met.
• PS3: Level 1 assays: PMID 32937241: Heterologous cells (CHO) - results - 53% LDLR expression, 50% binding, and 80% uptake. Expression and binding are below 70% of wild-type, so functional study is consistent with damaging effect. PS3 is met.
• PP3: REVEL = 0.933. It is above 0.75, so PP3 is met.
• PP4: Variant meet PM2. PMID: 16389549 (Humphries et al., 2005) - 1 case who fulfills Simon-Broome criteria for FH. So PP4 is met.

Not Met criteria codes

• PM1: Not in exon 4 and not a cysteine residue.
• PM3: No data available.
• PM5: 2 other missense variants in the same codon: - NM_000527.5(LDLR):c.1951G>A (p.Asp651Asn) (ClinVar ID 183128) - Uncertain significance by these guidelines - NM_000527.5(LDLR):c.1952A>T (p.Asp651Val) (ClinVar ID 252128) - Likely pathogenic by these guidelines There is no variant in the same codon classified as Pathogenic by these guidelines
• PM4: Not a in-frame deletions/insertions variant
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BA1: This variant is absent from gnomAD (gnomAD v2.1.1)
• BS2: No data available.
• BS1: This variant is absent from gnomAD (gnomAD v2.1.1)
• BS4: No data available.
• BS3: No experimental study available
• BP4: REVEL = 0.933 (>0.5)
• BP3: Not a in-frame deletions/insertions variant
• BP2: No data available.
• PVS1: Not a null variant (nonsense, frameshift, canonical +/- 1 or 2 splice sites, initiation codon, single or multiexon deletion)
• PS1: No other missense variant in the same codon resulting in the same amino acid change.
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: Variant meet PM2. PMID: 16389549 (Humphries et al., 2005) - 1 case who fulfills Simon-Broome criteria for FH.
• PP1: No data available.