Evidence Repository - Clinical Genome Resources

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.806G>A (p.Gly269Asp)

CA023767

161279 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 8d1fcbea-683f-43ab-9605-c55bbd040d84

Approved on: 2021-06-07

Published on: 2021-06-24

HGVS expressions

NM_000527.5:c.806G>A

NM_000527.5(LDLR):c.806G>A (p.Gly269Asp)

ENST00000558518.6:c.806G>A

ENST00000252444.9:n.1060G>A

ENST00000455727.6:c.314-716G>A

ENST00000535915.5:c.683G>A

ENST00000545707.5:c.425G>A

ENST00000557933.5:c.806G>A

ENST00000558013.5:c.806G>A

ENST00000558518.5:c.806G>A

ENST00000558528.1:n.321G>A

ENST00000560467.1:n.406G>A

NM_000527.4:c.806G>A

NM_001195798.1:c.806G>A

NM_001195799.1:c.683G>A

NM_001195800.1:c.314-716G>A

NM_001195803.1:c.425G>A

NM_001195798.2:c.806G>A

NM_001195799.2:c.683G>A

NM_001195800.2:c.314-716G>A

NM_001195803.2:c.425G>A

NC_000019.10:g.11106676G>A

CM000681.2:g.11106676G>A

NC_000019.9:g.11217352G>A

CM000681.1:g.11217352G>A

NC_000019.8:g.11078352G>A

NG_009060.1:g.22296G>A

Likely Benign

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Conflicting Evidence"

BS2 PP1_Moderate BP2

PM1 PM4 PM3 PM5 PM6 PM2 BA1 BS3 BS1 BS4 PS2 PS4 PS1 PS3 BP5 BP7 BP3 BP4 BP1 PVS1 PP4 PP3 PP2

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.806G>A (p.Gly269Asp) variant is classified as Likely benign for Familial Hypercholesterolemia by applying evidence codes (BS2, BP2 and PP1_Moderate) 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: BS2 - Identified in 7 heterozygous controls from ABraOM database, and 2 non-affected family members from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. BP2 - variant identified in 2 Index cases with heterozygous FH phenotype and a 2nd LDLR variant classified as Pathogenic by these guidelines. PP1_moderate - variant segregates with phenotype in 5 informative meiosis in 3 families from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. Variant has 1 Strong and 1 Supporting evidence codes towards Benign, enough to classify as Likely benign, and only 1 Moderate evidence code towards Pathogenic. The Benign criteria overwhelms the Pathogenic criteria, so we are confident in classifying this variant as Likely benign.

BS2

identified in 7 heterozygous controls from ABraOM database, and 2 non-affected family members from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. --- BS2 is Met

PP1_Moderate

variant segregates with phenotype in 5 informative meiosis in 3 families from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge: 5 affected family members have the variant. ---- PP1_Moderate is Met

BP2

variant identified in (1) 1 Index case with a heterozygous FH phenotype from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) and NM_000527.5(LDLR):c.551G>A p.Cys184Tyr (ClinVar ID 3739) variant - classified as Pathogenic by these guidelines. (2) 1 index case with an heterozygous FH phenotype from Laboratory of Genetics and Molecular Cardiology (#4) has 3 variants, 2 in cis --- do not use for BP2 (3) 1 index case with an Heterozygous FH phenotype from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge (#5) and NM_000527.5(LDLR):c.818-2A>G (ClinVar ID 251471) variant - classified as Pathogenic by these guidelines so BP2 is met

PM1

Missense at codon 269. PM2 is Not Met, it is not exon 4 or any of the 60 Cys residues listed, so PM1 is Not Met

PM4

Missense variant, not applicable

PM3

not identified in individuals with other variants and homozygous FH phenotype --- PM3 is Not Met

PM5

One more missense variant described in same codon: (1)NM_000527.4(LDLR):c.805G>A (p.Gly269Ser) (ClinVar ID 430763) - classified as VUS by these guidelines so PM5 is not met

PM6

no de novo cases were identified, so PM6 is Not Met

PM2

PopMax MAF = 0.001157 (0.116%) in latino exomes (gnomAD v2.1.1). FAF is not under 0.02%, so PM2 is Not Met

BA1

FAF = 0.0008476 (0.085%) in Latino/Admixed American exomes (gnomAD v2.1.1). FAF is not above 0.5%, so BA1 is Not Met.

BS3

Level 3 assays: PMID 21990180: Htz patients' lymphocytes, FACS assays - results - normal LDLR at cell surface (90%), LDL-LDLR binding (90%) and LDL uptake (100%) ---- whole cycle is not above 95% of wild-type activity, so BS3_supporting is Not Met

BS1

FAF = 0.0008476 (0.085%) in Latino/Admixed American exomes (gnomAD v2.1.1). FAF is not above 0.2%, so BS1 is Not Met.

BS4

Variant does not segregate with phenotype in 5 informative meiosis from 4 families from different labs (University of British Columbia and Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge): 5 affected family members do not have the variant. but only 1 family has 2 or more informative meiosis, so --- BS4 is Not Met

PS2

no de novo cases were identified, so PS2 is Not Met

PS4

variant does not meet PM2, so PS4 is Not Met

PS1

No variant described that leads to the same amino acid change, so PS1 is Not Met

PS3

Level 3 assays: PMID 21990180: Htz patients' lymphocytes, FACS assays - results - normal LDLR at cell surface (90%), LDL-LDLR binding (90%) and LDL uptake (100%) ---- whole cycle is not below 85% of wild-type activity, so PS3_supporting is Not Met

BP5

Not applicable

BP7

Missense variant, so BP7 is not applicable

BP3

Not applicable

BP4

REVEL = 0.661. It is not below 0.15, BP4 is Not Met

BP1

Not applicable

PVS1

Missense variant, PVS1 Not Met

PP4

Variant does not meet PM2, so PP4 is Not Met

PP3

REVEL = 0.661. It is not above 0.75, splicing evaluation required. Functional data on splicing not available. A) variant not on limits. B) variant is exonic and at least 50bp downstream from canonical acceptor site, but it does not create GT. C) there is a GT nearby. MES scores: variant cryptic = -12.89, wt cryptic = -4.54, canonical donor = 8.27. scores are negative, which means they are not used, so PP3 is Not Met

PP2

Not applicable

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