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.2098G>A (p.Asp700Asn)

Curation Version - 1.1
Curation History
JSON LD for Version 1.1

CA023633

200923 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 619b90b1-2290-483a-be56-533034937ce0

Approved on: 2022-03-25

Published on: 2022-07-12

HGVS expressions

NM_000527.5:c.2098G>A

NM_000527.5(LDLR):c.2098G>A (p.Asp700Asn)

NC_000019.10:g.11120480G>A

CM000681.2:g.11120480G>A

NC_000019.9:g.11231156G>A

CM000681.1:g.11231156G>A

NC_000019.8:g.11092156G>A

NG_009060.1:g.36100G>A

ENST00000558518.6:c.2098G>A

ENST00000252444.9:n.2352G>A

ENST00000455727.6:c.1594G>A

ENST00000535915.5:c.1975G>A

ENST00000545707.5:c.1606+247G>A

ENST00000557933.5:c.2098G>A

ENST00000558013.5:c.2098G>A

ENST00000558518.5:c.2098G>A

NM_000527.4:c.2098G>A

NM_001195798.1:c.2098G>A

NM_001195799.1:c.1975G>A

NM_001195800.1:c.1594G>A

NM_001195803.1:c.1606+247G>A

NM_001195798.2:c.2098G>A

NM_001195799.2:c.1975G>A

NM_001195800.2:c.1594G>A

NM_001195803.2:c.1606+247G>A

Likely Pathogenic

PS4_Supporting PP4 PM2 PS3_Moderate

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

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.2098G>A (p.Asp700Asn) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PS3_Moderate, 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 = 0.00006199 (0.006199%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1), so PM2 is Met. PS3_Moderate - Level 2 assays: PMID 34869944: Heterologous cells (CHO), FACS assays - result - 20% uptake. ---- functional study is consistent with damaging effect, so PS3_Moderate is Met. PS4_supporting - Variant meets PM2 and is identified in 2 unrelated index cases: 1 index case with DLCN>=6 from Color Health, Inc, and 1 index case with Simon Broome criteria (TC of 9.8 mmol/L and personal or family history of CHD) from UK (PMID: 23669246), so PS4_Supporting is Met. PP4 - Variant meets PM2 and is identified in 2 unrelated index cases (see PS4 for details), so PP4 is Met.

PS4_Supporting

Variant meets PM2 and is identified in 2 unrelated index cases: 1 index case with DLCN>=6 from Color Health, Inc, and 1 index case with Simon Broome criteria (TC of 9.8 mmol/L and personal or family history of CHD) from UK (PMID: 23669246), so PS4_Supporting is Met.

PP4

PM2

PopMax MAF = 0.00006199 (0.006199%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1), so PM2 is Met.

PS3_Moderate

Level 2 assays: PMID 34869944: Heterologous cells (CHO), FACS assays - result - 20% uptake. ---- functional study is consistent with damaging effect, so PS3_Moderate is Met.

BS4

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

BS3

Level 2 assays: PMID 34869944: Heterologous cells (CHO), FACS assays - result - 20% uptake. ---- functional study is consistent with damaging effect, so BS3 is not met.

BS1

FAF = 0.00001686 (0.001686%) in European (non-Finnish) exomes (gnomAD v2.1.1), so BS1 is not met.

BS2

Not observed in 140 000 individuals from the the UKBB, so BS2 is Not Met.

BP7

Variant is not synonymous, so BP7 is Not Met.

BP2

Variant identified in an index case with heterozygous FH phenotype (LDL<400) and LDLR c.1358+2T>A, but cannot determine if the variants are in trans, from GeneDx Inc., so BP2 is not met.

BP4

REVEL = 0.683. It is not below 0.50, so BP4 is not met.

PS1

No more missense variants at the same codon, so PS1 is Not Met.

PS2

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

BA1

FAF = 0.00001686 (0.001686%) in European (non-Finnish) exomes (gnomAD v2.1.1), so BA1 is not met.

PP1

Segregation data not reported, so PP1 is Not Met.

PP3

REVEL = 0.683, it is not above 0.75, so splicing evaluation is required. Functional data on splicing not available. A) variant not on limits B) does not create GT C) no GT nearby --- PP3 is not met.

PM6

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

PM4

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

PM5

2 other missense variants in the same codon: - NM_000527.5(LDLR):c.2099A>G (p.Asp700Gly) (ClinVar ID 252220) - Likely pathogenic by these guidelines - NM_000527.5(LDLR):c.2100C>G (p.Asp700Glu) (ClinVar ID 252221) - VUS by these guidelines No more missense variants at the same codon, classified as Pathogenic, so PM5 is Not Met.

PM3

Observed in 1 index case (phenotype not reported) with APOB c.10580G>A/p.(Arg3527Gln) classified as Pathogenic, from Ambry Genetics, 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

Variant is missense, so PVS1 is Not Met.

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.