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.718G>A (p.Glu240Lys)

CA023755

200920 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 54c170e0-5a9b-4b98-b1d4-806c3082ce85

HGVS expressions

NM_000527.5:c.718G>A

NM_000527.5(LDLR):c.718G>A (p.Glu240Lys)

NC_000019.10:g.11106588G>A

CM000681.2:g.11106588G>A

NC_000019.9:g.11217264G>A

CM000681.1:g.11217264G>A

NC_000019.8:g.11078264G>A

NG_009060.1:g.22208G>A

ENST00000558518.6:c.718G>A

ENST00000252444.9:n.972G>A

ENST00000455727.6:c.314-804G>A

ENST00000535915.5:c.595G>A

ENST00000545707.5:c.337G>A

ENST00000557933.5:c.718G>A

ENST00000558013.5:c.718G>A

ENST00000558518.5:c.718G>A

ENST00000558528.1:n.233G>A

ENST00000560467.1:n.318G>A

NM_000527.4:c.718G>A

NM_001195798.1:c.718G>A

NM_001195799.1:c.595G>A

NM_001195800.1:c.314-804G>A

NM_001195803.1:c.337G>A

NM_001195798.2:c.718G>A

NM_001195799.2:c.595G>A

NM_001195800.2:c.314-804G>A

NM_001195803.2:c.337G>A

Pathogenic

PS4 PP4 PP3 PM3 PM2

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

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.718G>A (p.Glu240Lys) variant is classified as U Pathogenic for Familial Hypercholesterolemia by applying evidence codes PP3, PM2, PS4, PM3, 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: PP3 - REVEL = 0.865. It is above 0.75, so PP3 is Met. PM2 - PopMax MAF = 0.00005418 (0.005418%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1), so PM2 is Met. PS4 - Variant meets PM2 and is identified in at least 11 unrelated index cases: 2 index cases with Simon Broome possible from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); 1 index case with DLCN>6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); 2 index cases with DLCN>6 from Robarts Research Institute; 2 index cases with DLCN>6 from Color Health, Inc; 2 index cases fulfilling the following criteria: children with a) TC >200 mg/dl or LDL >120 mg/dl and b) presence of primary hypercholesterolemia in 1st degree relatives with autosomal dominant mode of inheritance or c) family history of pCHD or d) presence of xanthomas in proband or in parents, from Greece (PMID: 25463123); at least 1 index case with Simon Broome criteria from China (PMID: 28235710); 1 index case with Definite FH (LDL >13 mmol/l and presence of xanthomas and hypercholesterolemia in both parents) from Italy (PMID: 32977124), so PS4 is Met. PM3 - Variant meets PM2 and is identified in an italian index case with homozygous FH phenotype (LDL>13 mmol/l) with another LDLR variant, in trans (PMID: 32977124). In PMID: 28965616 is identified an italian index case (phenotype not reported) with LDLR variant c.304C>T (p.Gln102*), classified as Pathogenic by these guidelines, but cannot determine if the variants are in trans (PMID: 28965616). Assuming that is the same homozygous index case (same lab), PM3 is Met. PP4 - Variant meets PM2 and is identified in at least 11 unrelated index cases as reported above, so PP4 is Met.

PS4

Variant meets PM2 and is identified in at least 11 unrelated index cases: 2 index cases with Simon Broome possible from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); 1 index case with DLCN>6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); 2 index cases with DLCN>6 from Robarts Research Institute; 2 index cases with DLCN>6 from Color Health, Inc; 2 index cases fulfilling the following criteria: children with a) TC >200 mg/dl or LDL >120 mg/dl and b) presence of primary hypercholesterolemia in 1st degree relatives with autosomal dominant mode of inheritance or c) family history of pCHD or d) presence of xanthomas in proband or in parents, from Greece (PMID: 25463123); at least 1 index case with Simon Broome criteria from China (PMID: 28235710); 1 index case with Definite FH (LDL >13 mmol/l and presence of xanthomas and hypercholesterolemia in both parents) from Italy (PMID: 32977124), so PS4 is Met.

PP4

PP3

REVEL = 0.865. It is above 0.75, so PP3 is Met.

PM3

Variant meets PM2 and is identified in an italian index case with homozygous FH phenotype (LDL>13 mmol/l) with another LDLR variant, in trans (PMID: 32977124). In PMID: 28965616 is identified an italian index case (phenotype not reported) with LDLR variant c.304C>T (p.Gln102*), classified as Pathogenic by these guidelines, but cannot determine if the variants are in trans (PMID: 28965616). Assuming that is the same homozygous index case (same lab), PM3 is Met.

PM2

PopMax MAF = 0.00005418 (0.005418%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1), so PM2 is Met.

BA1

FAF = 0.00002293 (0.002293%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1), so BA1 is not met.

PVS1

Variant is missense, so PVS1 is Not Met.

BS2

Not observed in 10000 normolipidemic individuals from Robarts Research Institute, so BS2 is note met.

BS4

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

BS3

Functional studies are performed in compound heterozygous patients cells or the type of assays are not validated, so BS3 is not applicable.

BS1

FAF = 0.00002293 (0.002293%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1), so BA1 is not met.

BP2

Observed in an index case (phenotype not reported) with another LDLR variant c.304C>T (p.Gln102*), classified as Pathogenic by these guidelines, but cannot determine if the variants are in trans (PMID: 28965616), so BP2 is Not Met.

BP4

REVEL = 0.865. It is not below 0.50, so BP4 is Not Met.

BP7

Variant is not synonymous, so BP7 is Not Met

PS2

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

PS3

Functional studies are performed in compound heterozygous patients cells or the type of assays are not validated, so PS3 is not applicable.

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.

PM1

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

PM4

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

PM5

No more missense variants at the same codon, so PM5 is Not Met.

PM6

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

Approved on: 2022-02-14

Published on: 2022-07-12

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