Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
Link to SEPIO compliant JSON-LD document

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

CA10585693

252127 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: f9cc13a9-0509-451a-a856-60c50af7c90d

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
ENST00000558518.6:c.1951G>T
ENST00000252444.9:n.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:n.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

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"
Met criteria codes 4
PS3 PP4 PP3 PM2
Not Met criteria codes 18
PVS1 PS2 PS4 PS1 PP1 BA1 PM6 PM3 PM1 PM4 PM5 BS2 BS4 BS3 BS1 BP2 BP3 BP4

Evidence Links 0

Expert Panel

Criteria Specification Information

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

Criteria Specification Approval History
Criteria Specifications for this VCEP
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
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.
PP4
Variant meet PM2. PMID: 16389549 (Humphries et al., 2005) - 1 case who fulfills Simon-Broome criteria for FH. So PP4 is met.
PP3
REVEL = 0.933. 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
PVS1
Not a null variant (nonsense, frameshift, canonical +/- 1 or 2 splice sites, initiation codon, single or multiexon deletion)
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.
PS1
No other missense variant in the same codon resulting in the same amino acid change.
PP1
No data available.
BA1
This variant is absent from gnomAD (gnomAD v2.1.1)
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
No data available.
PM1
Not in exon 4 and not a cysteine residue.
PM4
Not a in-frame deletions/insertions variant
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
BS2
No data available.
BS4
No data available.
BS3
No experimental study available
BS1
This variant is absent from gnomAD (gnomAD v2.1.1)
BP2
No data available.
BP3
Not a in-frame deletions/insertions variant
BP4
REVEL = 0.933 (>0.5)
Approved on: 2023-03-20
Published on: 2023-03-31
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