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.296C>G (p.Ser99Ter)

CA023685

161269 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: e668fde2-5aaa-456f-b07d-e4a3b84620f5

HGVS expressions

NM_000527.5:c.296C>G

NM_000527.5(LDLR):c.296C>G (p.Ser99Ter)

ENST00000558518.6:c.296C>G

ENST00000252444.9:n.550C>G

ENST00000455727.6:c.296C>G

ENST00000535915.5:c.190+2424C>G

ENST00000545707.5:c.296C>G

ENST00000557933.5:c.296C>G

ENST00000557958.1:n.382C>G

ENST00000558013.5:c.296C>G

ENST00000558518.5:c.296C>G

NM_000527.4:c.296C>G

NM_001195798.1:c.296C>G

NM_001195799.1:c.190+2424C>G

NM_001195800.1:c.296C>G

NM_001195803.1:c.296C>G

NM_001195798.2:c.296C>G

NM_001195799.2:c.190+2424C>G

NM_001195800.2:c.296C>G

NM_001195803.2:c.296C>G

NC_000019.10:g.11102769C>G

CM000681.2:g.11102769C>G

NC_000019.9:g.11213445C>G

CM000681.1:g.11213445C>G

NC_000019.8:g.11074445C>G

NG_009060.1:g.18389C>G

Pathogenic

PS4 PP4 PM2 PVS1 PS3_Supporting

PS2 PS1 PP3 PP2 PP1 PM3 PM4 PM1 PM5 PM6 BA1 BS2 BS4 BS3 BS1 BP4 BP1 BP2 BP3 BP5 BP7

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.296C>G (p.Ser99Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PVS1, PS4, PM2, PP4 and PS3_Supporting) 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: PVS1 - Variant is nonsense, causing a stop at codon 99. It is upstream of amino acid 830, so PVS1 is Met. PS4 - Variant meets PM2. Identified in over 20 unrelated clinical FH cases (PMID: 7718019). PM2 - PopMax MAF = 0.000008791 (0.0009%) in european non-finnish exomes (gnomAD v2.1.1). PP4 - Variant meets PM2. Identified in over 20 unrelated clinical FH cases (PMID: 7718019). PS3_supporting - Level 3 assays: PMID 19148831: Epstein-Barr virus transformed lymphocytes from htz patients, FACS and RNA assays - results - ~60% gene expression, LDL-LDLR uptake and protein at cell surface ---- results are below 85% of wild-type, so PS3_supporting is Met

PS4

Variant meets PM2. Identified in over 20 unrelated clinical FH cases (Clinical diagnosis according to Goldstein and Brown) from Norway (PMID: 7718019).

PP4

Variant meets PM2. Identified in over 20 unrelated clinical FH cases (Clinical diagnosis according to Goldstein and Brown) from Norway (PMID: 7718019). --- PP4 is Met

PM2

PopMax MAF = 0.000008791 (0.0009%) in european non-finnish exomes (gnomAD v2.1.1). MAF is under 0.02%, so PM2 is Met.

PVS1

Variant is nonsense, causing a stop at codon 99. It is upstream of amino acid 830, so PVS1 is Met

PS3_Supporting

Level 3 assays: PMID 19148831: Epstein-Barr virus transformed lymphocytes from htz patients, FACS and RNA assays - results - ~60% gene expression, LDL-LDLR uptake and protein at cell surface ---- results are below 85% of wild-type, so PS3_supporting is Met

PS2

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

PS1

Nonsense variant, PS1 not applicable

PP3

PVS1 is Met, so PP3 is not applicable

PP2

Not applicable

PP1

no family members were tested, so PP1 is Not Met

PM3

not identified in individuals with other variants, so PM3 is Not Met

PM4

Nonsense variant (PVS1 is Met), PM4 is Not Met

PM1

Nonsense variant, so PM1 is Not applicable

PM5

Nonsense variant, PM5 not applicable

PM6

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

BA1

No FAF, just total MAF = 0.000003976 (0.0004%) in european non-finnish exomes (gnomAD v2.1.1). MAF is not above 0.5%, so BA1 is Not Met.

BS2

no unaffected individuals identified with the variant, so BS2 is Not Met

BS4

no family members were tested, so BS4 is Not Met

BS3

Level 3 assays: PMID 19148831: Epstein-Barr virus transformed lymphocytes from htz patients, FACS and RNA assays - results - ~60% gene expression, LDL-LDLR uptake and protein at cell surface ---- whole cycle is not above 95%, so BS3_supporting is Not Met

BS1

No FAF, just total MAF = 0.000003976 (0.0004%) in european non-finnish exomes (gnomAD v2.1.1). MAF is not above 0.2%, so BS1 is Not Met.

BP4

PVS1 is Met, so BP4 is not applicable

BP1

Not applicable

BP2

not identified in individuals with other variants, so BP2 is Not Met

BP3

Not applicable

BP5

Not applicable

BP7

Nonsense variant, so BP7 is not applicable

Approved on: 2021-06-07

Published on: 2021-06-24

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