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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  • See Evidence submitted by expert panel for details.

Variant: NM_000527.5(LDLR):c.2251C>T (p.Arg751Trp)

CA039237

926358 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 5a8e52f7-674e-40db-b967-033cf18032a1

HGVS expressions

NM_000527.5:c.2251C>T
NM_000527.5(LDLR):c.2251C>T (p.Arg751Trp)
NC_000019.10:g.11123284C>T
CM000681.2:g.11123284C>T
NC_000019.9:g.11233960C>T
CM000681.1:g.11233960C>T
NC_000019.8:g.11094960C>T
NG_009060.1:g.38904C>T
ENST00000558518.6:c.2251C>T
ENST00000252444.9:n.2505C>T
ENST00000455727.6:c.1747C>T
ENST00000535915.5:c.2128C>T
ENST00000545707.5:c.1717C>T
ENST00000557933.5:c.2251C>T
ENST00000558013.5:c.2251C>T
ENST00000558518.5:c.2251C>T
NM_000527.4:c.2251C>T
NM_001195798.1:c.2251C>T
NM_001195799.1:c.2128C>T
NM_001195800.1:c.1747C>T
NM_001195803.1:c.1717C>T
NM_001195798.2:c.2251C>T
NM_001195799.2:c.2128C>T
NM_001195800.2:c.1747C>T
NM_001195803.2:c.1717C>T

Likely Benign

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Conflicting Evidence"
Met criteria codes 3
BP4 PM2 BS2
Not Met criteria codes 23
PS2 PS4 PS3 PS1 BP2 BP3 BP1 BP5 BP7 BA1 PP4 PP1 PP3 PP2 PM1 PM3 PM4 PM5 PM6 PVS1 BS4 BS3 BS1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
NM_000527.5(LDLR): c.2251C>T (p.Arg751Trp) variant is classified as Likely benign for Familial Hypercholesterolemia by applying evidence codes PM2, BS2 and BP4 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 = 0.0001202 (0.01202%) in African/African American exomes+genomes (gnomAD v2.1.1). BP4 - REVEL = 0.428, it is below 0.50, splicing evaluation required. Variant is exonic and at least 50bp downstream from canonical donor site, but it does not create AG/GT. BS2 - Variant identified in 717 heterozygotes and 72 homozygotes (PMID: 25414273). These subjects had the same level of LDLc as non-carriers (N=2408).
Met criteria codes
BP4
REVEL = 0.428, it is below 0.50, splicing evaluation required. Variant is exonic and at least 50bp downstream from canonical acceptor site, but it does not create AG/GT.
PM2
PopMax MAF = 0.0001202 (0.01202%) in African/African American exomes+genomes (gnomAD v2.1.1).
BS2
Variant identified in 717 heterozygotes and 72 homozygotes (PMID: 25414273). These subjects had the same level of LDLc as non-carriers (N=2408).
Not Met criteria codes
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
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
BP2
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
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
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
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
REVEL = 0.428
PP2
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
PM3
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
1 other missense variant in the same codon: - NM_000527.5(LDLR):c.2252G>A (p.Arg751Gln) (ClinVar ID 161286) - Uncertain significance by these guidelines There is no variant in the same codon classified as Pathogenic by these guidelines.
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
PMID: 25414273 - Level 2 assay - Heterologous cells (COS7), WB assay: mature LDLR expression ~ 63% Heterologous cells (HepG2) LDLR binding activity: 12% reduction in binding ability - activity is not above 90%.
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Approved on: 2022-05-26
Published on: 2022-06-30
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