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 label mismatch: LDLR vs undefined
  • 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.949G>A (p.Glu317Lys)

CA030891

251567 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 734fe7c6-d89f-4217-889a-c8fbf259726b
Approved on: 2025-03-25
Published on: 2025-03-25

HGVS expressions

NM_000527.5:c.949G>A
NM_000527.5(LDLR):c.949G>A (p.Glu317Lys)
NC_000019.10:g.11110660G>A
CM000681.2:g.11110660G>A
NC_000019.9:g.11221336G>A
CM000681.1:g.11221336G>A
NC_000019.8:g.11082336G>A
NG_009060.1:g.26280G>A
ENST00000252444.10:c.1207G>A
ENST00000559340.2:c.949G>A
ENST00000560467.2:c.941-854G>A
ENST00000558518.6:c.949G>A
ENST00000252444.9:c.1203G>A
ENST00000455727.6:c.445G>A
ENST00000535915.5:c.826G>A
ENST00000545707.5:c.568G>A
ENST00000557933.5:c.949G>A
ENST00000558013.5:c.949G>A
ENST00000558518.5:c.949G>A
ENST00000560467.1:c.541-854G>A
NM_000527.4:c.949G>A
NM_001195798.1:c.949G>A
NM_001195799.1:c.826G>A
NM_001195800.1:c.445G>A
NM_001195803.1:c.568G>A
NM_001195798.2:c.949G>A
NM_001195799.2:c.826G>A
NM_001195800.2:c.445G>A
NM_001195803.2:c.568G>A
More

Uncertain Significance

Met criteria codes 4
PM2 PS4_Supporting PP4 PP3
Not Met criteria codes 13
PVS1 BA1 PM1 PM4 PM5 BS1 BP7 BP3 BP4 BP1 PS1 PP1 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

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
The NM_000527.5(LDLR):c.949G>A (p.Glu317Lys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 25 March 2025. The supporting evidence is as follows: PM2: PopMax MAF = 0.0001867 (0.01867%) in European (non-Finnish) (gnomAD v4.1.0). PP3: REVEL = 0.899. PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 4 index cases with DLCN score >=6, after alternative causes of high cholesterol were excluded: 1 case from Robarts Research Institute, Canada; 1 case from PMID 33418990 (Meshkov et al., 2021), Russia; 2 cases from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille, France.
Met criteria codes
PM2
PopMax MAF = 0.0001867 (0.01867%) in European (non-Finnish) (gnomAD v4.0). PM2 is met since PopMax MAF<0.02%.
PS4_Supporting
Variant meets PM2 and is identified in at least 4 index cases who fulfill criteria for FH, after alternative causes of high cholesterol were excluded: 1 index case presenting DLCN>=6 from Robarts Research Institute; 1 index case fulfilling DLCN>=6 (PMID: 33418990); 2 cases with DLCN score >=6 from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille.
PP4
Variant meets PM2 and is identified in at least 1 index case fulfilling DLCN>=6, after alternative causes of high cholesterol were excluded, from Robarts Research Institute.
PP3
REVEL = 0.899. It is above 0.75, so PP3 is met.
Not Met criteria codes
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
Variant segregates with FH phenotype in 2 informative meioses in 2 families - one family member positive for variant with LDL-C >75th percentile (from Robarts Research Institute) and one family member negative for variant with LDL-C <50th percentile from Laboratory of Genetics and Molecular Cardiology. However, non-segregation is observed in 6 family members negative for variant with LDL-C >75th percentile (5 from Laboratory of Genetics and Molecular Cardiology, 1 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière)), and therefore PP1 has not been applied.
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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