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]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_000527.5(LDLR):c.337G>A (p.Glu113Lys)

CA043209

237872 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: a09d8e79-7df9-4d5f-b357-ebd7eff7a82c
Approved on: 2024-02-23
Published on: 2025-06-30

HGVS expressions

NM_000527.5:c.337G>A
NM_000527.5(LDLR):c.337G>A (p.Glu113Lys)
NC_000019.10:g.11105243G>A
CM000681.2:g.11105243G>A
NC_000019.9:g.11215919G>A
CM000681.1:g.11215919G>A
NC_000019.8:g.11076919G>A
NG_009060.1:g.20863G>A
ENST00000252444.10:c.595G>A
ENST00000559340.2:c.337G>A
ENST00000560467.2:c.337G>A
ENST00000558518.6:c.337G>A
ENST00000252444.9:c.591G>A
ENST00000455727.6:c.314-2149G>A
ENST00000535915.5:c.214G>A
ENST00000545707.5:c.314-1322G>A
ENST00000557933.5:c.337G>A
ENST00000558013.5:c.337G>A
ENST00000558518.5:c.337G>A
NM_000527.4:c.337G>A
NM_001195798.1:c.337G>A
NM_001195799.1:c.214G>A
NM_001195800.1:c.314-2149G>A
NM_001195803.1:c.314-1322G>A
NM_001195798.2:c.337G>A
NM_001195799.2:c.214G>A
NM_001195800.2:c.314-2149G>A
NM_001195803.2:c.314-1322G>A
More

Pathogenic

Met criteria codes 6
PM3 PM1 PM2 PP1_Strong PS4_Moderate PP4
Not Met criteria codes 20
PM4 PM5 PM6 BA1 BS2 BS4 BS3 BS1 BP3 BP4 BP1 BP2 BP5 BP7 PS2 PS3 PS1 PVS1 PP3 PP2

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.2

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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.337G>A (p.Glu113Lys) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PP1_Strong, PM1, PM2, PM3, PS4_Moderate and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows: PM2: PopMax MAF = 0.0001 (0.01%) in South Asian (gnomAD v4.0.0). PM1: Variant meets PM2 and is missense in exon 4. PS4_Moderate, PP4: Variant meets PM2 and is identified in at least 8 unrelated index cases who fulfill criteria for FH (1 case with possible FH by Simon Broome criteria from the Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic; 1 case with possible FH by Simon Broome criteria and 1 case with DLCN score >=6 from Service de Biochimie de Biologie Moléculaire, Hospices Civils de Lyon, France; 1 case with possible FH by Simon Broome criteria from PMID 17539906 (Taylor et al., 2007), UK; 1 case with DLCN score >=6 from PMID 16250003 (Fouchier et al., 2005), The Netherlands; 1 case with possible FH by Simon Broome criteria from PMID 10807540 (Wu et al., 2000), USA; 2 cases with definite FH by Simon Broome criteria from PMID 34456049 (Marco-Benedi et al., 2022). PP1_Strong: Variant segregates with FH phenotype in 8 informative meioses in 1 family in PMID: 10807540 (Wu et al., 2000), USA: 7 affected family members have the variant. PM3: Variant meets PM2 and is identified in an index case with a homozygous FH phenotype (10 yo with LDLc= 14.9 mmol/L); variant is in compound heterozygosity with c.2389G>T (p.Val797Leu), which is classified as Likely pathogenic by these guidelines and is in trans, from Service de Biochimie de Biologie Moléculaire, Hospices Civils de Lyon, France (VCI).
Met criteria codes
PM3
PM3 - Variant meets PM2 and is identified in an index case with a homozygous FH phenotype (10 yo with LDLc= 14.9 mmol/L); variant is in compound heterozygosity with c.2389G>T (p.Val797Leu), which is classified as Likely pathogenic by these guidelines and is in trans (1 of 2 variants was found in mother - hypercholesterolemic father not tested); from Service de Biochimie de Biologie Moléculaire, Hospices Civils de Lyon, France (VCI).
PM1
PM1 - Variant meets PM2 and is missense in exon 4.
PM2
PM2 - PopMax MAF = 0.0001 (0.01%) in South Asian (gnomAD v4.0.0)
PP1_Strong
PP1_strong - Variant segregates with FH phenotype in 8 informative meioses in 1 family in PMID: 10807540 (Wu et al., 2000), USA: 7 affected family members have the variant;
PS4_Moderate
PS4_Moderate - Variant meets PM2 and is identified in 8 unrelated index cases - 1 case with Simon Broome criteria of possible FH from the Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), Czech Republic; 1 case with Simon-Broome criteria of possible FH and 1 case with DLCN criteria>=6 from Service de Biochimie de Biologie Moléculaire, Hospices Civils de Lyon, France; 1 case with Simon-Broome criteria of possible FH in PMID: 17539906 (Taylor et al., 2007), UK; 1 case with DLCN criteria>=6 in PMID: 16250003 (Fouchier et al., 2005), The Netherlands; 1 case with Simon-Broome criteria of possible FH in PMID: 10807540 (Wu et al., 2000), USA; 2 cases with Simon-Broome criteria of definite FH in PMID: 34456049 (Marco-Benedi et al., 2022);
PP4
PP4 - Variant meets PM2 and is identified in at least 1 index case who fulfills clinical criteria for FH, after alternative causes of high cholesterol were excluded (see PS4 for details).
Not Met criteria codes
PM4
Not applicable
PM5
PM5 - There is 1 variant in the same codon [c.337G>T, p.(Glu113Ter] but it is not missense
PM6
No de novo cases were identified
BA1
Not applicable
BS2
Variant not identified in normolipidemic individuals
BS4
BS4 - Variant does not segregate with FH phenotype in 2 informative meiosis from 2 families from different labs (Service de Biochimie de Biologie Moléculaire, Hospices Civils de Lyon, France/PMID: 10807540 (Wu et al., 2000), USA: 2 affected family members do not have the variant, however no unaffected relatives were positive for the variant, so BS4 cannot be applied.
BS3
BS3 - Functional studies are not available.
BS1
Not applicable
BP3
Not applicable
BP4
BP4 - REVEL = 0.658; it is not below 0.5, so BP4 is not met.
BP1
Not applicable
BP2
Not applicable
BP5
Not applicable
BP7
Not applicable
PS2
No de novo cases were identified
PS3
PS3 - Functional studies are not available.
PS1
Not applicable
PVS1
Not applicable
PP3
PP3 - REVEL=0.658, splicing evaluation required. A) Variant not on limits B) does not create AG C) there is an AG nearby MES scores: variant cryptic site = -7.58, wt cryptic site = -16.76, canonical acceptor site = 8.16. Ratio variant cryptic/wt cryptic score: -7.58/-16.76 = 0.45 --- it is not above 1.1 Ratio variant cryptic/canonical acceptor score: -7.58/8.16 = -0.92--- it is not above 0.9 ---PP3 is not met.
PP2
Not applicable
Curation History
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