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.2473A>G (p.Asn825Asp)

CA10585869

252340 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 39d43aca-1749-4ce4-9fa8-d7ff03c0e481

HGVS expressions

NM_000527.5:c.2473A>G

NM_000527.5(LDLR):c.2473A>G (p.Asn825Asp)

NC_000019.10:g.11129596A>G

CM000681.2:g.11129596A>G

NC_000019.9:g.11240272A>G

CM000681.1:g.11240272A>G

NC_000019.8:g.11101272A>G

NG_009060.1:g.45216A>G

ENST00000558518.6:c.2473A>G

ENST00000252444.9:n.2727A>G

ENST00000455727.6:c.1969A>G

ENST00000535915.5:c.2350A>G

ENST00000545707.5:c.1939A>G

ENST00000557933.5:c.2535A>G

ENST00000558013.5:c.2473A>G

ENST00000558518.5:c.2473A>G

ENST00000560628.1:n.108+1942A>G

NM_000527.4:c.2473A>G

NM_001195798.1:c.2473A>G

NM_001195799.1:c.2350A>G

NM_001195800.1:c.1969A>G

NM_001195803.1:c.1939A>G

NM_001195798.2:c.2473A>G

NM_001195799.2:c.2350A>G

NM_001195800.2:c.1969A>G

NM_001195803.2:c.1939A>G

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

PP4 PP3 PM5 PM2 PS4_Supporting

PS3

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5 (LDLR):c.2473A>G (p.Asn825Asp) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PS4_Supporting, PM5) 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: This variant is absent from gnomAD (gnomAD v2.1.1). PP3: REVEL = 0.93. PP4: Variant meets PM2 and is identified in >1 index cases who fulfil FH diagnostic criteria after alternative causes of high cholesterol were excluded. PS4_Supporting: Variant meets PM2 and is identified in 2 unrelated index cases who fulfil FH diagnostic criteria. One index case fulfil criteria of TC > 8mmol/l and strong family history of CAD, Laurie et al, 2004, Canterbury Health Laboratories, New Zealand, PMID: 15556094. One index case with DLCN score ≥6, Meshkov et al, 2021, National Medical Research Center for Therapy and Preventive Medicine, Russia, PMID: 33418990. PM5: Two other missense variants in the same codon: NM_000527.5 (LDLR):c.2475C>G (p.Asn825Lys), (ClinVarID 161265), is classified as Likely Pathogenic; NM_000527.5 (LDLR):c.2475C>A (p.Asn825Lys), (ClinVarID 252341), is classified as Pathogenic by these guidelines, therefore PM5 is met.

PP4

Variant meets PM2 and is identified in >1 index cases who fulfil FH diagnostic criteria after alternative causes of high cholesterol were excluded.

PP3

REVEL = 0.93

PM5

Two other missense variants in the same codon: NM_000527.5 (LDLR):c.2475C>G (p.Asn825Lys), (ClinVarID 161265), is classified as Likely Pathogenic; NM_000527.5 (LDLR):c.2475C>A (p.Asn825Lys), (ClinVarID 252341), is classified as Pathogenic by these guidelines, therefore PM5 is met.

PM2

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

PS4_Supporting

Variant meets PM2 and is identified in 2 unrelated index cases who fulfil FH diagnostic criteria. One index case fulfil criteria of TC > 8mmol/l and strong family history of CAD, Laurie et al, 2004, Canterbury Health Laboratories, New Zealand, PMID: 15556094. One index case with DLCN score ≥6, Meshkov et al, 2021, National Medical Research Center for Therapy and Preventive Medicine, Russia, PMID: 33418990.

PS3

Functional data is not available.

Approved on: 2023-03-20

Published on: 2023-03-31

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