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]

Link to SEPIO compliant JSON-LD document

Variant: NM_000527.5(LDLR):c.2043C>G (p.Cys681Trp)

CA10585743

252188 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: c12a6a0d-1d06-4705-8036-67b2e5a31e81

HGVS expressions

NM_000527.5:c.2043C>G

NM_000527.5(LDLR):c.2043C>G (p.Cys681Trp)

ENST00000558518.6:c.2043C>G

ENST00000252444.9:n.2297C>G

ENST00000455727.6:c.1539C>G

ENST00000535915.5:c.1920C>G

ENST00000545707.5:c.1606+192C>G

ENST00000557933.5:c.2043C>G

ENST00000558013.5:c.2043C>G

ENST00000558518.5:c.2043C>G

NM_000527.4:c.2043C>G

NM_001195798.1:c.2043C>G

NM_001195799.1:c.1920C>G

NM_001195800.1:c.1539C>G

NM_001195803.1:c.1606+192C>G

NM_001195798.2:c.2043C>G

NM_001195799.2:c.1920C>G

NM_001195800.2:c.1539C>G

NM_001195803.2:c.1606+192C>G

NC_000019.10:g.11120425C>G

CM000681.2:g.11120425C>G

NC_000019.9:g.11231101C>G

CM000681.1:g.11231101C>G

NC_000019.8:g.11092101C>G

NG_009060.1:g.36045C>G

Pathogenic

PP1_Strong PP4 PP3 PM2 PM1

PS2 PS4 PS3 PS1 PVS1 PP2 BA1 PM6 BS4 BS3 BS1 PM3 PM4 PM5 BS2 BP5 BP7 BP2 BP3 BP4 BP1

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

NM_000527.5(LDLR):c.2043C>G (p.Cys681Trp) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PP1_Strong, PM1, PM2, PP3 and PP4) 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: PP1_strong - Variant segregates with FH phenotype in 7 informative meioses in 1 family from PMID: 16092059. PM1 - Variant meets PM2 and is one of listed Cysteine. PM2 - No population data was found for this allele in gnomAD (gnomAD v2.1.1). PP3 - REVEL: 0,83. PP4 - Variant meet PM2. PMID: 16092059 - 1 case who fulfills Simon-Broome criteria for FH.

PP1_Strong

Variant segregates with FH phenotype in 7 informative meioses in 1 family from PMID: 16092059.

PP4

Variant meet PM2. PMID: 16092059 - 1 case who fulfills Simon-Broome criteria for FH.

PP3

REVEL: 0,83. Score is above 0,75.

PM2

No population data was found for this allele in gnomAD (gnomAD v2.1.1).

PM1

Variant meets PM2 and is one of listed Cysteine. S-S bond with Cys667.

PS2

No de novo cases were identified.

PS4

PMID: 16092059 - 1 case with Simon-Broome criteria. At least 2 unrelated cases are needed for PS4.

PS3

No functional assays performed/found - not applicable.

PS1

Variant meets PM1, so not applicable.

PVS1

Missense variant. Not applicable.

PP2

Not applicable.

BA1

No population data was found for this allele in gnomAD (gnomAD v2.1.1).

PM6

No de novo cases were identified.

BS4

No non-segregations were identified/found.

BS3

No functional assays performed/found - not applicable.

BS1

No population data was found for this allele in gnomAD (gnomAD v2.1.1).

PM3

Not identified in individuals with other variants.

PM4

Missense variant. Not applicable.

PM5

Variant meets PM1, so not applicable.

BS2

No unaffected individuals identified with the variant.

BP5

Not applicable.

BP7

Missense variant. Not applicable.

BP2

Not identified in individuals with other variants.

BP3

Not applicable.

BP4

REVEL: 0,83. Score is not below 0,50.

BP1

Not applicable.

Approved on: 2021-06-18

Published on: 2021-06-24

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