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.2546C>A (p.Ser849Ter)

CA10585878

252350 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 0c970ab1-3278-4f04-af3a-5b8859e99901

HGVS expressions

NM_000527.5:c.2546C>A

NM_000527.5(LDLR):c.2546C>A (p.Ser849Ter)

ENST00000558518.6:c.2546C>A

ENST00000252444.9:n.2800C>A

ENST00000455727.6:c.2042C>A

ENST00000535915.5:c.2423C>A

ENST00000545707.5:c.2012C>A

ENST00000557933.5:c.2608C>A

ENST00000558013.5:c.2546C>A

ENST00000558518.5:c.2546C>A

ENST00000560628.1:n.108+2015C>A

NM_000527.4:c.2546C>A

NM_001195798.1:c.2546C>A

NM_001195799.1:c.2423C>A

NM_001195800.1:c.2042C>A

NM_001195803.1:c.2012C>A

NM_001195798.2:c.2546C>A

NM_001195799.2:c.2423C>A

NM_001195800.2:c.2042C>A

NM_001195803.2:c.2012C>A

NC_000019.10:g.11129669C>A

CM000681.2:g.11129669C>A

NC_000019.9:g.11240345C>A

CM000681.1:g.11240345C>A

NC_000019.8:g.11101345C>A

NG_009060.1:g.45289C>A

Likely Pathogenic

PP4 PVS1_Moderate PM2 PS4_Supporting

PS2 PS3 PS1 BP2 BP3 BP4 BP1 BP5 BP7 BA1 PP1 PP3 PP2 PM3 PM1 PM4 PM5 PM6 BS2 BS4 BS3 BS1

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.2546C>A (p.Ser849Ter) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PVS1_Moderate, PP4 and PS4_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: PM2 - No population data was found for this allele in gnomAD (gnomAD v2.1.1). PVS1_moderate - Variant is nonsense after amino acid 830 (NM_000527.5:p.Lys830). PP4 - Variant meets PM2. Variant identified in 2 index FH cases (1 case from Color laboratory with Simon-Broome criteria; 1 case with Simon-Broome criteria published in PMID: 26892515). PS4_supporting - Variant meets PM2. Variant identified in 2 index cases (1 case from Color laboratory with Simon-Broome criteria; 1 case with Simon-Broome criteria published in PMID: 26892515).

PP4

Variant meets PM2. Variant identified in 2 index FH cases (1 case from Color laboratory with Simon-Broome criteria; 1 case with Simon-Broome criteria published in PMID: 26892515).

PVS1_Moderate

Variant is nonsense after amino acid 830 (NM_000527.5:p.Lys830).

PM2

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

PS4_Supporting

Variant meets PM2. Variant identified in 2 index cases (1 case from Color laboratory with Simon-Broome criteria; 1 case with Simon-Broome criteria published in PMID: 26892515).

PS2

No de novo cases were identified.

PS3

No functional assays performed/found - not applicable.

PS1

Nonsense variant. Not applicable.

BP2

Not identified in individuals with other variants.

BP3

Not applicable.

BP4

Nonsense variant that meets PVS1. Not applicable.

BP1

Not applicable.

BP5

Not applicable

BP7

Nonsense variant. Not applicable.

BA1

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

PP1

Family members not tested.

PP3

Nonsense variant that meets PVS1. Not applicable.

PP2

Not applicable.

PM3

Not identified in individuals with other variants.

PM1

Nonsense variant. Not applicable.

PM4

Nonsense variant. Not applicable.

PM5

Nonsense variant. Not applicable.

PM6

No de novo cases were identified.

BS2

No unaffected individuals identified with the variant.

BS4

Family members not tested.

BS3

No functional assays performed/found - not applicable.

BS1

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

Approved on: 2021-06-22

Published on: 2021-06-24

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