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.1444G>C (p.Asp482His)

CA10585454

251844 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: c4514ebd-5f3b-4eb3-b62b-68702b42de00

Approved on: 2023-06-23

Published on: 2024-09-25

HGVS expressions

NM_000527.5:c.1444G>C

NM_000527.5(LDLR):c.1444G>C (p.Asp482His)

NC_000019.10:g.11113620G>C

CM000681.2:g.11113620G>C

NC_000019.9:g.11224296G>C

CM000681.1:g.11224296G>C

NC_000019.8:g.11085296G>C

NG_009060.1:g.29240G>C

ENST00000252444.10:c.1702G>C

ENST00000559340.2:c.1444G>C

ENST00000560467.2:c.1324G>C

ENST00000558518.6:c.1444G>C

ENST00000252444.9:c.1698G>C

ENST00000455727.6:c.940G>C

ENST00000535915.5:c.1321G>C

ENST00000545707.5:c.1063G>C

ENST00000557933.5:c.1444G>C

ENST00000558013.5:c.1444G>C

ENST00000558518.5:c.1444G>C

ENST00000559340.1:c.165G>C

ENST00000560467.1:c.924G>C

NM_000527.4:c.1444G>C

NM_001195798.1:c.1444G>C

NM_001195799.1:c.1321G>C

NM_001195800.1:c.940G>C

NM_001195803.1:c.1063G>C

NM_001195798.2:c.1444G>C

NM_001195799.2:c.1321G>C

NM_001195800.2:c.940G>C

NM_001195803.2:c.1063G>C

Likely Pathogenic

PP4 PP3 PM5 PM2 PS3_Moderate PS4_Supporting

PS2 PS1 PP1 PM3 PM1 PM4 PM6 BA1 BS2 BS4 BS3 BS1 BP2 BP3 BP4 PVS1

Evidence Links 1

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.1444G>C (p.Asp482His) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS3_Moderate, PM2, PM5, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023. PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PP3: REVEL=0.993. PM5: 3 other missense variants in the same codon: - NM_000527.5(LDLR):c.1444G>A (p.Asp482Asn) (ClinVar ID 161284) - Pathogenic by these guidelines; - NM_000527.5(LDLR):c.1444G>T (p.Asp482Tyr) (ClinVar ID 251845) - Uncertain significance by these guidelines; - NM_000527.5(LDLR):c.1445A>G (p.Asp482Gly) (ClinVar ID 251846) - Likely Pathogenic by these guidelines; There is 1 variant in the same codon classified as Pathogenic by these guidelines. PS3_Moderate: Level 2 assay: PMID 31587492 (Kizhakkedath P et al., 2019) - HEK-293T cells. In immunoblots of the mutants, only the precursor form was observed (~120 kDa) and the mature receptor form was absent. PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 2 index cases who fulfill Simon Broome criteria for FH (1 case in PMID 11313767 (Heath KE et al., 2001), 1 case in PMID 10559517 (Graham CA et al., 1999)).

PP4

Variant meets PM2 and is identified in 2 unrelated index cases who fulfill clinical criteria for FH (see PS4 for details), after alternative causes of high cholesterol were excluded.

PP3

REVEL=0.993. It is above 0.75, so PP3 is met.

PM5

3 other missense variants in the same codon: - NM_000527.5(LDLR):c.1444G>A (p.Asp482Asn) (ClinVar ID 161284) - Pathogenic by these guidelines - NM_000527.5(LDLR):c.1444G>T (p.Asp482Tyr) (ClinVar ID 251845) - Uncertain significance by these guidelines - NM_000527.5(LDLR):c.1445A>G (p.Asp482Gly) (ClinVar ID 251846) - Likely Pathogenic by these guidelines There is 1 variant in the same codon classified as Pathogenic by these guidelines.

PM2

This variant is absent from gnomAD (gnomAD v2.1.1). So, PM2 is met.

PS3_Moderate

Level 2 assays PMID 31587492- HEK-293T cells. In immunoblots of the mutants, only the precursor form was observed (~120 kDa) and the mature receptor form was absent. So, PS3_Moderate was met.

Level 2 assay- HeLa cells and HEK-293T cells. In immunoblots of the mutants D482H, only the precursor form was observed (~120 kDa) and the mature receptor form was absent. PubMed:31587492

PS4_Supporting

Variant meets PM2 and is identified in 2 index cases (1 case with Simon-Broome criteria of FH in PMID: 11313767 (Heath KE et al., 2001), 1 case with Simon-Broome criteria of FH in PMID: 10559517 (Graham CA et al., 1999)). So, PS4_Supporting is met.

PS2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PS1

No other missense variant in the same codon with the same amino acid change.

PP1

No evidence available

PM3

No evidence available

PM1

Not in exon 4. Not a cysteine residue.

PM4

No in-frame deletions/insertions

PM6

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BA1

This variant is absent from gnomAD (gnomAD v2.1.1).

BS2

No evidence available

BS4

No evidence available

BS3

No evidence available

BS1

This variant is absent from gnomAD (gnomAD v2.1.1).

BP2

No evidence available

BP3

No in-frame deletions/insertions

BP4

REVEL=0.993.

PVS1

Not a null variant

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