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.889A>C (p.Asn297His)

CA10585178

251505 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 65a6d45c-084c-48d6-9c9c-010f092c2acd

HGVS expressions

NM_000527.5:c.889A>C

NM_000527.5(LDLR):c.889A>C (p.Asn297His)

NC_000019.10:g.11107463A>C

CM000681.2:g.11107463A>C

NC_000019.9:g.11218139A>C

CM000681.1:g.11218139A>C

NC_000019.8:g.11079139A>C

NG_009060.1:g.23083A>C

ENST00000558518.6:c.889A>C

ENST00000252444.9:n.1143A>C

ENST00000455727.6:c.385A>C

ENST00000535915.5:c.766A>C

ENST00000545707.5:c.508A>C

ENST00000557933.5:c.889A>C

ENST00000558013.5:c.889A>C

ENST00000558518.5:c.889A>C

ENST00000558528.1:n.404A>C

ENST00000560467.1:n.489A>C

NM_000527.4:c.889A>C

NM_001195798.1:c.889A>C

NM_001195799.1:c.766A>C

NM_001195800.1:c.385A>C

NM_001195803.1:c.508A>C

NM_001195798.2:c.889A>C

NM_001195799.2:c.766A>C

NM_001195800.2:c.385A>C

NM_001195803.2:c.508A>C

Uncertain Significance

PM2 PS4_Supporting PP4

PM6 PM5 PM4 PM3 PM1 PVS1 BS4 BS3 BS1 BS2 BP7 BP2 BP4 BA1 PS1 PS2 PS3 PP1 PP3

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 1.1

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.889A>C (p.Asn297His) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PS4_supporting and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - PopMax MAF = 1/24948 = 0.00004 (0.004%) in African/African-American 8692 exomes plus 16256 genomes (gnomAD v2.1.1), so PM2 is Met. PS4_supporting - Variant meets PM2 and is identified in at least 1 index case with DLCN>6 (definite heterozygous hypercholesterolemia) from The Netherlands (PMID: 16250003) and at least 1 index case with DLCN>6 from Spain (PMID: 19318025), so PS4_Supporting is Met. PP4 - Variant meets PM2 and is identified in at least 1 index case with DLCN>6 (definite heterozygous hypercholesterolemia) from The Netherlands (PMID: 16250003) and at least 1 index case with DLCN>6 from Spain (PMID: 19318025), so PP4 is Met.

PM2

PopMax MAF = 1/24948 = 0.00004 (0.004%) in African/African-American 8692 exomes plus 16256 genomes (gnomAD v2.1.1), so PM2 is Met.

PS4_Supporting

Variant meets PM2 and is identified in at least 1 index case with DLCN>6 (definite heterozygous hypercholesterolemia) from The Netherlands (PMID: 16250003) and at least 1 index case with DLCN>6 from Spain (PMID: 19318025), so PS4_Supporting is Met.

PP4

PM6

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

PM5

2 missense variants in the same codon: - NM_000527.4(LDLR):c.890A>G (p.Asn297Ser) (ClinVar ID: 441198) - VUS by these guidelines - NM_000527.4(LDLR):c.890A>C (p.Asn297Thr) (ClinVar ID: 441197) - VUS by these guidelines There is 2 variants in the same codon classified as VUS by these guidelines, so PM5 is Not Met.

PM4

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

PM3

Allele Data not reported, so PM3 is Not Met.

PM1

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

PVS1

PMID: 16250003 criteria not specified

BS4

Segregation data not reported, so BS4 is Not Met.

BS3

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

BS1

No FAF, total MAF = 0.00003189 (0.003189%) (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

Allele Data not reported, so BP2 is Not Met.

BP4

REVEL = 0.583, it is not below 0.50, so BP4 is Not Met.

BA1

No FAF, total MAF = 0.00003189 (0.003189%) (gnomAD v2.1.1), so BA1 is Not Met.

PS1

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

PS2

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

PS3

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

PP1

Segregation data not reported, so PP1 is Not Met.

PP3

REVEL = 0.583, 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 an GT nearby MES scores: variant cryptic = -4.52, wt cryptic = -4.52, canonical donor = 10.49. Ratio variant cryptic/wt cryptic: -4.52/-4.52 = 1 --- it is not above 1.1 Ratio variant cryptic/canonical donor: -4.52/10.49 = -0.43--- it is not above 0.9 Variant is not predicted to alter splicing, so PP3 is Not Met.

Approved on: 2022-02-28

Published on: 2022-07-12

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