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]

Variant: NM_000527.5(LDLR):c.1412G>A (p.Arg471Lys)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA404085845

430776 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: e08668bc-f415-4946-8fe7-cf1ef88a62c6

Approved on: 2023-06-23

Published on: 2025-06-30

HGVS expressions

NM_000527.5:c.1412G>A

NM_000527.5(LDLR):c.1412G>A (p.Arg471Lys)

NC_000019.10:g.11113588G>A

CM000681.2:g.11113588G>A

NC_000019.9:g.11224264G>A

CM000681.1:g.11224264G>A

NC_000019.8:g.11085264G>A

NG_009060.1:g.29208G>A

ENST00000252444.10:c.1670G>A

ENST00000559340.2:c.1412G>A

ENST00000560467.2:c.1292G>A

ENST00000558518.6:c.1412G>A

ENST00000252444.9:c.1666G>A

ENST00000455727.6:c.908G>A

ENST00000535915.5:c.1289G>A

ENST00000545707.5:c.1031G>A

ENST00000557933.5:c.1412G>A

ENST00000558013.5:c.1412G>A

ENST00000558518.5:c.1412G>A

ENST00000559340.1:c.133G>A

ENST00000560467.1:c.892G>A

NM_000527.4:c.1412G>A

NM_001195798.1:c.1412G>A

NM_001195799.1:c.1289G>A

NM_001195800.1:c.908G>A

NM_001195803.1:c.1031G>A

NM_001195798.2:c.1412G>A

NM_001195799.2:c.1289G>A

NM_001195800.2:c.908G>A

NM_001195803.2:c.1031G>A

Uncertain Significance

BP4 PP4 PM2

BS4 BS3 BS1 BS2 BP7 BP2 PS4 PS2 PS3 PS1 PP1 PP3 PVS1 PM3 PM1 PM4 PM5 PM6 BA1

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specification: ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.2

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.1412G>A (p.Arg471Lys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). BP4: REVEL = 0.412, it is below 0.50, splicing evaluation required. Functional data on splicing not available. A) variant not on limits B) does not create AG or GT C) variant is exonic and there are 2 AG nearby; #1 MES scores: variant cryptic = -4.92, wt cryptic = -10.07, canonical acceptor= 6.76; #2 MES scores: variant cryptic = -7.95, wt cryptic = -13.41, canonical acceptor= 6.76. Scores are negative, so variant is not predicted to alter splicing. PP4: Variant meets PM2 and is identified in at least 1 case with definite FH by DLCN criteria from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583828.1), after alternative causes of high cholesterol were excluded.

BP4

REVEL = 0.412, it is below 0.50, splicing evaluation required. Functional data on splicing not available. A) variant not on limits B) does not create AG or GT C) variant is exonic and there is 2 AG nearby #1 MES scores: variant cryptic = -4.92, wt cryptic = -10.07, canonical acceptor= 6.76. Ratio variant cryptic/wt cryptic: -4.92/-10.07 = 0.49 --- it is not above 1.1 Ratio variant cryptic/canonical acceptor: -4.92/6.76 = -0.73--- it is not above 0.9 #2 MES scores: variant cryptic = -7.95, wt cryptic = -13.41, canonical acceptor= 6.76. Ratio variant cryptic/wt cryptic: -7.95/-13.41 = 0.59 --- it is not above 1.1 Ratio variant cryptic/canonical acceptor: -4.92/6.76 = -0.73--- it is not above 0.9 Variant is not predicted to alter splicing. ---BP4 is met.

PP4

Variant meets PM2 and is identified in at last 1 case with DLCN criteria of definite FH from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583828.1), after alternative causes of high cholesterol were excluded, so PP4 is Met.

PM2

This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met.

BS4

Lack of segregation data not reported, so BS4 is Not Met.

BS3

There are no functional studies reported for this variant, so BS3 is not met.

BS1

This variant is absent from gnomAD (gnomAD v2.1.1), so BS1 is not met.

BS2

Case-control data not reported, so BS2 is Not Met.

BP7

Variant is not synonymous, so BP7 is Not Met.

BP2

Not observed in trans with other LP/P variants, so BP2 is Not Met.

PS4

Variant meets PM2 and is identified in at least 1 index case with DLCN criteria of definite FH from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583828.1), after alternative causes of high cholesterol were excluded, PS4_supporting is Not Met.

PS2

de novo occurrence data not reported, so PS2 is Not Met.

PS3

There are no functional studies reported for this variant, so PS3 is not met.

PS1

No more missense variants that lead to the same amino acid change, so PS1 is Not Met.

PP1

Segregation data not reported, so PP1 is Not Met.

PP3

REVEL = 0.412, it is not above 0.75, splicing evaluation required. Functional data on splicing not available. A) variant not on limits B) does not create AG or GT C) variant is exonic and there is 2 AG nearby #1 MES scores: variant cryptic = -4.92, wt cryptic = -10.07, canonical acceptor= 6.76. Ratio variant cryptic/wt cryptic: -4.92/-10.07 = 0.49 --- it is not above 1.1 Ratio variant cryptic/canonical acceptor: -4.92/6.76 = -0.73--- it is not above 0.9 #2 MES scores: variant cryptic = -7.95, wt cryptic = -13.41, canonical acceptor= 6.76. Ratio variant cryptic/wt cryptic: -7.95/-13.41 = 0.59 --- it is not above 1.1 Ratio variant cryptic/canonical acceptor: -4.92/6.76 = -0.73--- it is not above 0.9 Variant is not predicted to alter splicing. ---PP3 is not met.

PVS1

Variant is missense, so PVS1 is Not Met.

PM3

Not observed in trans with other LP/P variants, so PM3 is Not Met.

PM1

Variant meets PM2 but is not located in exon 4 or alters a cysteine residue, so PM1 is Not Met.

PM4

Variant meets PM2 and is missense, so PM4 is Not Met.

PM5

1 other missense variant in the same codon: - NM_000527.5(LDLR):c.1411A>G (p.Arg471Gly) (ClinVar ID 251829) - Likely pathogenic by these guidelines There is no variant in the same codon classified as Pathogenic by these guidelines.

PM6

de novo occurrence data not reported, so PM6 is Not Met.

BA1

This variant is absent from gnomAD (gnomAD v2.1.1), so BA1 is not met.

Curation History

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