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.1284C>G (p.Asn428Lys)

CA10585385

251766 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 4736fd6c-8af0-45ab-9291-81a7022b17c8

Approved on: 2023-06-23

Published on: 2024-10-02

HGVS expressions

NM_000527.5:c.1284C>G

NM_000527.5(LDLR):c.1284C>G (p.Asn428Lys)

NC_000019.10:g.11113375C>G

CM000681.2:g.11113375C>G

NC_000019.9:g.11224051C>G

CM000681.1:g.11224051C>G

NC_000019.8:g.11085051C>G

NG_009060.1:g.28995C>G

ENST00000252444.10:c.1542C>G

ENST00000559340.2:c.1284C>G

ENST00000560467.2:c.1164C>G

ENST00000558518.6:c.1284C>G

ENST00000252444.9:c.1538C>G

ENST00000455727.6:c.780C>G

ENST00000535915.5:c.1161C>G

ENST00000545707.5:c.903C>G

ENST00000557933.5:c.1284C>G

ENST00000558013.5:c.1284C>G

ENST00000558518.5:c.1284C>G

ENST00000559340.1:c.5C>G

ENST00000560173.1:n.283C>G

ENST00000560467.1:c.764C>G

NM_000527.4:c.1284C>G

NM_001195798.1:c.1284C>G

NM_001195799.1:c.1161C>G

NM_001195800.1:c.780C>G

NM_001195803.1:c.903C>G

NM_001195798.2:c.1284C>G

NM_001195799.2:c.1161C>G

NM_001195800.2:c.780C>G

NM_001195803.2:c.903C>G

Uncertain Significance

PS4_Supporting PP4 PM2

BP4 PS3 PP1 PP3 PM5

Evidence Links 0

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.1284C>G (p.Asn428Lys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, 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. The supporting evidence is as follows: PM2: Variant is absent from gnomAD (gnomAD v2.1.1). PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 5 index cases who fulfill criteria for FH (1 case with total cholesterol >8 mmol/L and family history of hypercholesterolemia or classical clinical stigmata of FH from PMID 11857755 (Bunn et al., 2002), New Zealand; 1 case with total cholesterol >90th percentile and clinical features of FH or family history of early CHD from PMID 11845603 (Vergotine et al., 2001), South Africa; 1 case with DLCN score >=6 from PMID 11810272 (Fouchier et al., 2001), the Netherlands; 1 case with LDL >95th percentile, plus two of: presence of xanthomata, CAD in proband or family history of CAD or high LDL, from PMID 11668640 (Garcia-Garcia et al., 2001) Spain; 1 case with LDLC 6.5 mmol/L, presence of xanthomas, and history of angioplasty or bypass surgery from PMID 11005141 (Khoo et al., 2000), Malaysia.

PS4_Supporting

Variant meets PM2 and is identified in 5 index cases who fulfil FH criteria reported in PubMed. PMID 11857755: one index case fulfil TC>8 mmol/l and family history of hypercholesterolemia or classical clinical stigmata of FH, by Bunn et al, 2002, from Canterbury health laboratories, Christchurch, New Zealand. PMID 11845603: one index case fulfil TC≥90th percentile and had clinical features of FH or family history of early CHD, by Vergotine et al, 2001, from University of Stellenbosch, South Africa (in Jewish population, Table 1). PMID 11810272: one case fulfil DLCN criteria for FH, by Fouchier et al, 2001, from Academic medical center, Amsterdam, the Netherlands. PMID 11668640: one case fulfil LDLC>95th percentile, plus two of: presence of xanthomata, CAD in proband or family history of CAD or high LDL, by Garcia-Garcia 2001 from Instituto de investigaciones citologicas, Valencia, Spain. PMID 11005141: one case (Malay) had LDLC 6.5 mmol/l, presence of xanthomas, and history of angioplasty or bypass surgery (Table 2 and 3), by Khoo et al, 2000, from Heart foundation Malaysia and Academic medical center Amsterdam, the Netherlands.

PP4

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

PM2

Variant is absent from gnomAD (gnomAD v2.1.1).

BP4

REVEL=0.718, it is not above 0.75, splicing evaluation required. Functional data on splicing not available. MES performed: A) Variant is not on limits. B) Variant is on limits and creates AG. Var de novo score/Wt score= -5.07/6.59=-0.77, it is <0.8. REVEL is not below 0.5, therefore PP3/BP4 is not met. C) Variant is on limits and nearby a GT (aac/gGTGGTC). Var cryptic/Wt cryptic score= 1.06-8.71= -0.12, it is <1.1, Var cryptic/Wt score=1.06/9.60=0.11, it is <0.9. REVEL is not below 0.5, therefor PP3/BP4 is not met.

PS3

Functional data is not available.

PP1

PMID 11845603 by Vergotine et al, 2001: at least two relatives tested positive for the variant with unspecified phenotype. PMID11238294 by Tai et al, 2001: only one relative carries this variant had high LDLC (Figure 1 and Table 2).

PP3

REVEL=0.718, it is not above 0.75, splicing evaluation required.

PM5

One other variant at same codon: LDLR:c.1283A>G (p.Asn428Ser) is classified as VUS by these guidelines, therefore PM5 is not met.

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