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.2099A>G (p.Asp700Gly)

CA10585773

252220 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 2a2037a5-71ae-40c0-bd4e-5330cb1f1f50

HGVS expressions

NM_000527.5:c.2099A>G

NM_000527.5(LDLR):c.2099A>G (p.Asp700Gly)

NC_000019.10:g.11120481A>G

CM000681.2:g.11120481A>G

NC_000019.9:g.11231157A>G

CM000681.1:g.11231157A>G

NC_000019.8:g.11092157A>G

NG_009060.1:g.36101A>G

ENST00000558518.6:c.2099A>G

ENST00000252444.9:n.2353A>G

ENST00000455727.6:c.1595A>G

ENST00000535915.5:c.1976A>G

ENST00000545707.5:c.1606+248A>G

ENST00000557933.5:c.2099A>G

ENST00000558013.5:c.2099A>G

ENST00000558518.5:c.2099A>G

NM_000527.4:c.2099A>G

NM_001195798.1:c.2099A>G

NM_001195799.1:c.1976A>G

NM_001195800.1:c.1595A>G

NM_001195803.1:c.1606+248A>G

NM_001195798.2:c.2099A>G

NM_001195799.2:c.1976A>G

NM_001195800.2:c.1595A>G

NM_001195803.2:c.1606+248A>G

Likely Pathogenic

PM2 PS4_Supporting PS3 PP4 PP3

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

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.2099A>G (p.Asp700Gly) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PS3, PS4_Supporting, PM2, PP3 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: PS3 - Level 1 assays: PMID 32015373: Heterologous cells (CHO), FACS assays - result - 35% cell surface LDLR, 60% binding and 52% uptake. ---- activity is below 70% of wild-type, so PS3 is Met. PS4_Supporting - Variant meets PM2 and is identified in 2 unrelated index cases: 1 index case with FH criteria (CT>95th percentile, plus tendon xanthomata or pCHD in proband or 1st degree and hypercholesterolemia in family) from Spain (PMID: 11668640) and at least 1 index case with SB criteria for FH from China (PMID: 22353362), so PS4_Supporting is Met. PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met. PP3 - REVEL = 0.875. It is above 0.75, so PP3 is Met. PP4 - Variant meets PM2 and is identified in 2 unrelated index cases who fulfill clinical criteria for FH from several labs (see PS4 for details), so PP4 is Met.

PM2

This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met.

PS4_Supporting

Variant meets PM2 and is identified in 2 unrelated index cases: 1 index case with FH criteria (CT>95th percentile, plus tendon xanthomata or pCHD in proband or 1st degree and hypercholesterolemia in family) from Spain (PMID: 11668640) and at least 1 index case with SB criteria for FH from China (PMID: 22353362), so PS4_Supporting is Met.

PS3

Level 1 assays: PMID 32015373: Heterologous cells (CHO), FACS assays - result - 35% cell surface LDLR, 60% binding and 52% uptake. ---- activity is below 70% of wild-type, so PS3 is Met.

PP4

PP3

REVEL = 0.875. It is above 0.75, so PP3 is Met.

PM6

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

PM3

Not observed in trans with other LP/P variants, 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.

PM5

2 other missense variants in the same codon: - NM_000527.5(LDLR):c.2098G>A (p.Asp700Asn) (ClinVar ID 200923) - 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.

PM4

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

PVS1

Variant is missense, so PVS1 is Not Met.

BS2

No control individuals tested, so BS2 is Not Met.

BS3

Level 1 assays: PMID 32015373: Heterologous cells (CHO), FACS assays - result - 35% cell surface LDLR, 60% binding and 52% uptake. ---- activity is below 70% of wild-type, so BS3 is not met.

BS4

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

BS1

No population data was found for this variant in gnomAD (gnomAD v2.1.1), so BS1 is Not Met.

BP7

Variant is not synonymous, so BP7 is Not Met.

BP2

Not observed in trans with other LP/P variants, so BP2 is Not Met.

BP4

REVEL = 0.875. It is not below 0.50, so BP4 is Not Met.

PS2

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

PS1

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

PP1

Segregation data not reported, so PP1 is Not Met.

BA1

No population data was found for this variant in gnomAD (gnomAD v2.1.1), so BA1 is Not Met.

Approved on: 2022-03-25

Published on: 2022-04-19

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