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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  • See Evidence submitted by expert panel for details.

Variant: NM_000527.5(LDLR):c.2096C>T (p.Pro699Leu)

CA038525

252219 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: ea33bc95-d102-418a-b019-83d258dcad77

HGVS expressions

NM_000527.5:c.2096C>T
NM_000527.5(LDLR):c.2096C>T (p.Pro699Leu)
NC_000019.10:g.11120478C>T
CM000681.2:g.11120478C>T
NC_000019.9:g.11231154C>T
CM000681.1:g.11231154C>T
NC_000019.8:g.11092154C>T
NG_009060.1:g.36098C>T
ENST00000558518.6:c.2096C>T
ENST00000252444.9:n.2350C>T
ENST00000455727.6:c.1592C>T
ENST00000535915.5:c.1973C>T
ENST00000545707.5:c.1606+245C>T
ENST00000557933.5:c.2096C>T
ENST00000558013.5:c.2096C>T
ENST00000558518.5:c.2096C>T
NM_000527.4:c.2096C>T
NM_001195798.1:c.2096C>T
NM_001195799.1:c.1973C>T
NM_001195800.1:c.1592C>T
NM_001195803.1:c.1606+245C>T
NM_001195798.2:c.2096C>T
NM_001195799.2:c.1973C>T
NM_001195800.2:c.1592C>T
NM_001195803.2:c.1606+245C>T

Uncertain Significance

Met criteria codes 3
PP1_Strong BS4 PP3
Not Met criteria codes 23
PVS1 BA1 BS2 BS3 BS1 BP5 BP7 BP2 BP3 BP4 BP1 PS2 PS4 PS3 PS1 PP4 PP2 PM6 PM2 PM3 PM1 PM4 PM5

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
NM_000527.5(LDLR):c.2096C>T (p.Pro699Leu) variant is classified as Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (BS4, PP1_Strong and PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: BS4 - Variant does not segregate with FH phenotype in 11 informative meioses in 6 families (Laboratory of Genetics and Molecular Cardiology). PP1_strong - Variant segregates with FH phenotype in 58 informative meioses in 9 families from Laboratory of Genetics and Molecular Cardiology. PP3 - REVEL: 0,92.
Met criteria codes
PP1_Strong
Variant segregates with FH phenotype in 58 informative meioses (segregations) in 9 families from Laboratory of Genetics and Molecular Cardiology.
BS4
Variant does not segregate with FH phenotype in 11 informative meioses (nonsegregations) in 6 families (Laboratory of Genetics and Molecular Cardiology).
PP3
REVEL: 0,92. Score is above 0,75.
Not Met criteria codes
PVS1
Missense variant. Not applicable.
BA1
FAF = 0.00004981 (0.004981%) in African exomes (gnomAD v2.1.1). FAF is not above 0.5%
BS2
Variant identified in two unaffected heterozygous carriers from Laboratory of Genetics and Molecular Cardiology. At least 3 htz unaffected carriers are needed for adding this point. BS2 not met.
BS3
No functional assays performed/found - not applicable.
BS1
FAF = 0.00004981 (0.004981%) in African exomes (gnomAD v2.1.1). FAF is not above 0.2%
BP5
Not applicable.
BP7
Missense variant. Not applicable.
BP2
No proven pathogenic variants in double heterozygocity: - One carrier also htz for PCSK9 c.1976G>T, p.Arg659Leu (ClinVar ID 297705) (Uncertain significance in ClinVar) found by Ambry Genetics. - One carrier also htz for APOB p.Leu3436Val (VUS) and - other carrier htz for PCSK9 c.1069C>T, p.Arg357Cys (ClinVar ID 575758)(Conflicting classifications in ClinVar) found by Laboratory of Genetics and Molecular Cardiology.
BP3
Not applicable.
BP4
REVEL: 0,92. Score is not below 0,50.
BP1
Not applicable.
PS2
No de novo cases were identified.
PS4
Variant does not meet PM2, not applicable
PS3
No functional assays performed/found - not applicable.
PS1
No variant described that leads to the same amino acid change.
PP4
Variant does not meet PM2, so not applicable
PP2
Not applicable.
PM6
No de novo cases were identified.
PM2
PopMax MAF = 0.0003606 (0.036%) in African exomes (gnomAD v2.1.1). FAF is not below 0.02%
PM3
Variant does not meet PM2, so not applicable.
PM1
Missense at codon 699. PM2 is not Met, it is not exon 4 or any of the 60 Cys residues listed. Not applicable.
PM4
Missense variant. Not applicable.
PM5
No other variant found in this codon in ClinVar database (assessed 4 June 2020).
Approved on: 2021-06-18
Published on: 2021-06-24
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