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

CA023633

200923 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
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
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Likely Pathogenic

Met criteria codes 4
PS3_Moderate PP4 PM2 PS4_Supporting
Not Met criteria codes 18
PS1 PS2 BP7 BP2 BP4 BA1 PP1 PP3 PVS1 PM4 PM5 PM3 PM1 PM6 BS2 BS4 BS3 BS1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.1

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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.
Met criteria codes
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.
PP4
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 PP4 is Met.
PM2
PopMax MAF = 0.00006199 (0.006199%) in European (non-Finnish) exomes+genomes (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 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.
Not Met criteria codes
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.
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.
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.
PVS1
Variant is missense, so PVS1 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.
PM6
de novo occurrence data not reported, so PM6 is Not Met.
BS2
Not observed in 140 000 individuals from the the UKBB, so BS2 is Not 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.
Curation History
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