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]
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Variant: NM_000527.5(LDLR):c.1952A>T (p.Asp651Val)

CA10585694

252128 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 761b16f7-9cf4-42d6-a358-64a3b3108dd7

HGVS expressions

NM_000527.5:c.1952A>T
NM_000527.5(LDLR):c.1952A>T (p.Asp651Val)
NC_000019.10:g.11120198A>T
CM000681.2:g.11120198A>T
NC_000019.9:g.11230874A>T
CM000681.1:g.11230874A>T
NC_000019.8:g.11091874A>T
NG_009060.1:g.35818A>T
ENST00000558518.6:c.1952A>T
ENST00000252444.9:n.2206A>T
ENST00000455727.6:c.1448A>T
ENST00000535915.5:c.1829A>T
ENST00000545707.5:c.1571A>T
ENST00000557933.5:c.1952A>T
ENST00000558013.5:c.1952A>T
ENST00000558518.5:c.1952A>T
ENST00000559340.1:n.533A>T
NM_000527.4:c.1952A>T
NM_001195798.1:c.1952A>T
NM_001195799.1:c.1829A>T
NM_001195800.1:c.1448A>T
NM_001195803.1:c.1571A>T
NM_001195798.2:c.1952A>T
NM_001195799.2:c.1829A>T
NM_001195800.2:c.1448A>T
NM_001195803.2:c.1571A>T

Uncertain Significance

Met criteria codes 2
PP3 PM2
Not Met criteria codes 20
PS2 PS4 PS3 PS1 PP4 PP1 PM6 PM3 PM1 PM4 PM5 PVS1 BA1 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.1952A>T (p.Asp651Val) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and 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 = 0.793. It is above 0.75, so PP3 is met.
Met criteria codes
PP3
REVEL = 0.793. 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
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
No data available.
PS3
No data available.
PS1
No other missense variant in the same codon resulting in the same amino acid change.
PP4
No data available.
PP1
No data available.
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.1951G>T (p.Asp651Tyr) (ClinVar ID 252127) - Uncertain significance by these guidelines There are no variant in the same codon classified as Pathogenic by these guidelines.
PVS1
Not a null variant (nonsense, frameshift, canonical +/- 1 or 2 splice sites, initiation codon, single or multiexon deletion)
BA1
This variant is absent from gnomAD (gnomAD v2.1.1).
BS2
No data available.
BS4
No data available.
BS3
No data 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 = 0.793 (>0.5)
Approved on: 2023-03-20
Published on: 2023-03-31
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