Evidence Repository
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.268G>A (p.Asp90Asn)

CA042604

251105 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 5eb6bd54-ae4e-4b33-9b7c-222467e9a8f8

HGVS expressions

NM_000527.5:c.268G>A
NM_000527.5(LDLR):c.268G>A (p.Asp90Asn)
NC_000019.10:g.11102741G>A
CM000681.2:g.11102741G>A
NC_000019.9:g.11213417G>A
CM000681.1:g.11213417G>A
NC_000019.8:g.11074417G>A
NG_009060.1:g.18361G>A
ENST00000558518.6:c.268G>A
ENST00000252444.9:n.522G>A
ENST00000455727.6:c.268G>A
ENST00000535915.5:c.190+2396G>A
ENST00000545707.5:c.268G>A
ENST00000557933.5:c.268G>A
ENST00000557958.1:n.354G>A
ENST00000558013.5:c.268G>A
ENST00000558518.5:c.268G>A
NM_000527.4:c.268G>A
NM_001195798.1:c.268G>A
NM_001195799.1:c.190+2396G>A
NM_001195800.1:c.268G>A
NM_001195803.1:c.268G>A
NM_001195798.2:c.268G>A
NM_001195799.2:c.190+2396G>A
NM_001195800.2:c.268G>A
NM_001195803.2:c.268G>A

Pathogenic

Met criteria codes 6
PP4 PM2 PM5_Strong PS3_Moderate PP1_Moderate PS4_Moderate
Not Met criteria codes 20
PS2 PS1 PP3 PP2 BA1 PM6 PM3 PM1 PM4 PVS1 BS2 BS4 BS3 BS1 BP5 BP7 BP2 BP3 BP4 BP1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
The NM_000527.5(LDLR):c.268G>A (p.Asp90Asn) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM5_Strong, PM2, PP1_Moderate, PS3_Moderate, PS4_Moderate and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM5_strong - there are 4 other missense variants is the same codon: - NM_000527.5(LDLR):c.268G>T (p.Asp90Tyr) - classified as Likely pathogenic​ by the FH VCEP, with these guidelines - NM_000527.5(LDLR):c.269A>C (p.Asp90Ala) - Likely pathogenic by these guidelines - NM_000527.5(LDLR):c.269A>G (p.Asp90Gly) - Pathogenic by these guidelines - NM_000527.5(LDLR):c.270T>A (p.Asp90Glu) - Pathogenic by these guidelines --- There are 2 variants classified as Pathogenic, so PM5_Strong is met. PP1_moderate - Variant segregates with phenotype in 4 informative meiosis from different labs: - 1 unaffected family member does not have the variant, from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); - 3 informative meiosis from 1 family from PMID 12837857 (Chang et al. 2003): 1 relative has the variant and phenotype (III:1), plus 2 relatives do not have the variant and do not have the phenotype (II:1 and III:2) 4 informative meiosis, so PP1_Moderate is met. PM2 - PopMax MAF = 0.0008019 (0.08019%) in East Asian (gnomAD v2.1.1), but this is a founder variant in East Asian populations, so PM2 can be met in this instance. PS3_moderate - Level 2 FS: Chang et al., 2003 (PMID:12837857): Heterologous cells (COS-7), FACS assays - results: 55% LDLR cell surface and uptake. Binding is not studied, so not all cycle is studied (level 2 and not level 1) ---- functional study is consistent with damaging effect, activity is below 70% of wild-type, so PS3_Moderate is met. PS4_moderate - variant meets PM2 and was identified in: - 1 index case who fulfills Simon Broome criteria of possible FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), Czech Republic; - 3 unrelated index cases, all with Dutch lipid clinic network >=6, from Robarts Research Institute, Canada; - at least 1 index case with DLCN score of definite FH from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583645.1 in ClinVar), France; - 1 index case who fulfills SB criteria of at least possible FH from PMID 9259195 (Day et al., 1997), UK; - 1 index case who fulfills SB criteria of at least possible FH from PMID 25962062 (Han et al., 2015), Korea; - 2 unrelated index cases who fulfill SB criteria of possible FH (TC>8mmol/L, plus CAD) from PMID 12837857 (Chang et al., 2003), Taiwan, China; 9 cases, so PS4_Moderate is met. PP4 - variant meets PM2 and was identified in 9 unrelated index cases from different labs (see PS4 for details), so PP4 is met.
Met criteria codes
PP4
variant meets PM2 and was identified in: - 1 index case who fulfills Simon Broome criteria of possible FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), Czech Republic; - 3 unrelated index cases, all with Dutch lipid clinic network >=6, from Robarts Research Institute, Canada; - at least 1 index case with DLCN score of definite FH from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583645.1 in ClinVar), France; - 1 index case who fulfills SB criteria of at least possible FH from PMID 9259195 (Day et al., 1997), UK; - 1 index case who fulfills SB criteria of at least possible FH from PMID 25962062 (Han et al., 2015), Korea; - 2 unrelated index cases who fulfill SB criteria of possible FH (TC>8mmol/L, plus CAD) from PMID 12837857 (Chang et al., 2003), Taiwan, China so PP4 is met
PM2
PopMax MAF = 0.0008019 (0.08019%) in East Asian (gnomAD v2.1.1), but this is a founder variant in East Asian populations, so PM2 can be met in this instance
PM5_Strong
4 other missense variants is the same codon: - NM_000527.5(LDLR):c.268G>T (p.Asp90Tyr) - classified as Likely pathogenic​ by the FH VCEP, with these guidelines - NM_000527.5(LDLR):c.269A>C (p.Asp90Ala) - Likely pathogenic by these guidelines - NM_000527.5(LDLR):c.269A>G (p.Asp90Gly) - Pathogenic by these guidelines - NM_000527.5(LDLR):c.270T>A (p.Asp90Glu) - Pathogenic by these guidelines There are 2 variants classified as Pathogenic, so PM5_Strong is met
PS3_Moderate
Level 2 FS: Chang et al., 2003 (PMID:12837857): Heterologous cells (COS-7), FACS assays - results: 55% LDLR cell surface and uptake. Binding is not studied, so not all cycle is studied (level 2 and not level 1) ---- functional study is consistent with damaging effect, activity is below 70% of wild-type, so PS3_Moderate is met
PP1_Moderate
Variant segregates with phenotype in 4 informative meiosis from different labs: - 1 unaffected family member does not have the variant, from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); - 3 informative meiosis from 1 family from PMID 12837857 (Chang et al. 2003): 1 relative has the variant and phenotype (III:1), plus 2 relatives do not have the variant and do not have the phenotype (II:1 and III:2) 4 informative meiosis, so PP1_Moderate is met
PS4_Moderate
variant meets PM2 and was identified in: - 1 index case who fulfills Simon Broome criteria of possible FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), Czech Republic; - 3 unrelated index cases, all with Dutch lipid clinic network >=6, from Robarts Research Institute, Canada; - at least 1 index case with DLCN score of definite FH from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583645.1 in ClinVar), France; - 1 index case who fulfills SB criteria of at least possible FH from PMID 9259195 (Day et al., 1997), UK; - 1 index case who fulfills SB criteria of at least possible FH from PMID 25962062 (Han et al., 2015), Korea; - 2 unrelated index cases who fulfill SB criteria of possible FH (TC>8mmol/L, plus CAD) from PMID 12837857 (Chang et al., 2003), Taiwan, China (- at least 1 index case with Simon-Broome criteria of at least possible FH from PMID 21376320 (Chiou et al., 2011), Taiwan, China <-- do not consider to avoid double counting;) 9 cases, so PS4_Moderate is met
Not Met criteria codes
PS2
no de novo occurrence
PS1
no other missense variant leads to the same amino acid change in the same codon, so not met
PP3
REVEL = 0.738. It is not above 0.75, so splicing evaluation is needed: Functional data on splicing not available. A) not on limits B) does not create GT C) variant is exonic, there is no AG nearby, but there is a GT nearby: MES scores: variant cryptic = -0.00, wt cryptic = 5.51, canonical donor = 9.90. Variant cryptic score is 0, so it is not used. PP3 is not met
PP2
not applicable
BA1
FAF = 0.0004174 (0.04174%) in East Asian exomes (gnomAD v2.1.1). It is not above 0.5%, so not met
PM6
no de novo occurrence
PM3
variant not identified in index cases with more than 1 variant, so not met
PM1
variant does not meet PM2, is not in exon 4 and does not alter Cys, so not met
PM4
variant is missense, so not met
PVS1
variant is missense and not in initiation codon, so not met
BS2
not identified in normolipidemic individuals, so not met
BS4
Variant does not segregate with phenotype in 1 informative meiosis: 1 affected family member does not have the variant from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) -- not enough, so BS4 is not met
BS3
no level FS: Chang et al., 2003 (PMID:12837857): Heterologous cells (COS-7), FACS assays - results: 55% LDLR cell surface and uptake. Binding is not studied, so not all cycle is studied so BS3 is not met
BS1
FAF = 0.0004174 (0.04174%) in East Asian exomes (gnomAD v2.1.1). It is not above 0.2%, so not met
BP5
not applicable
BP7
variant is missense, so not met
BP2
variant not identified in index cases with more than 1 variant, so not met
BP3
no applicable
BP4
REVEL = 0.738. It is not below 0.50, so BP4 is not met
BP1
not applicable
Approved on: 2022-08-28
Published on: 2022-08-28
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