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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  • 'cspec' property is found but contains no ID!
  • See Evidence submitted by expert panel for details.

Variant: NM_000527.5(LDLR):c.2252G>A (p.Arg751Gln)

CA023654

161286 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 4c3500b5-196e-41cb-9c85-e39a63577757

HGVS expressions

NM_000527.5:c.2252G>A
NM_000527.5(LDLR):c.2252G>A (p.Arg751Gln)
NC_000019.10:g.11123285G>A
CM000681.2:g.11123285G>A
NC_000019.9:g.11233961G>A
CM000681.1:g.11233961G>A
NC_000019.8:g.11094961G>A
NG_009060.1:g.38905G>A
ENST00000558518.6:c.2252G>A
ENST00000252444.9:n.2506G>A
ENST00000455727.6:c.1748G>A
ENST00000535915.5:c.2129G>A
ENST00000545707.5:c.1718G>A
ENST00000557933.5:c.2252G>A
ENST00000558013.5:c.2252G>A
ENST00000558518.5:c.2252G>A
NM_000527.4:c.2252G>A
NM_001195798.1:c.2252G>A
NM_001195799.1:c.2129G>A
NM_001195800.1:c.1748G>A
NM_001195803.1:c.1718G>A
NM_001195798.2:c.2252G>A
NM_001195799.2:c.2129G>A
NM_001195800.2:c.1748G>A
NM_001195803.2:c.1718G>A

Uncertain Significance

Met criteria codes 3
PM2 PS4_Supporting PP4
Not Met criteria codes 23
PS2 PS3 PS1 PM6 PM3 PM1 PM4 PM5 BA1 PVS1 BP5 BP7 BP2 BP3 BP4 BP1 BS4 BS3 BS1 BS2 PP1 PP3 PP2

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.2252G>A (p.Arg751Gln) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, 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 = 0.0001602 (0.01602%) in African/African American exomes+genomes (gnomAD v2.1.1). PS4_supporting - Variant meets PM2 and is identified in 2 unrelated index cases (1 case published in PMID: 16250003 (Fouchier et al., 2005), Netherlands; 1 case published in PMID: 16159606 (Graham et al., 2005), United Kingdom). PP4 - Variant meets PM2. PMID: 16159606 - 1 case who fulfills Simon-Broome criteria for FH.
Met criteria codes
PM2
PopMax MAF = 0.0001602 (0.01602%) in African/African American exomes+genomes (gnomAD v2.1.1).
PS4_Supporting
Variant meets PM2 and is identified in 2 unrelated index cases (1 case published in PMID: 16250003 (Fouchier et al., 2005), Netherlands; 1 case published in PMID: 16159606 (Graham et al., 2005), United Kingdom).
PP4
Variant meet PM2. PMID: 16159606 - 1 case who fulfills Simon-Broome criteria for FH.
Not Met criteria codes
PS2
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
PM6
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
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
1 other missense variant in the same codon: - NM_000527.5(LDLR):c.2251C>T (p.Arg751Trp) (ClinVar ID 926358) - Uncertain significance by these guidelines There is no variant in the same codon classified as Pathogenic by these guidelines.
BA1
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
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
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
BP4
REVEL = 0.506, it is not below 0.5.
BP1
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
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
BS2
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 = 0.506, it is not above 0.75, splicing evaluation required. Functional data on splicing not available. Variant is exonic and at least 50bp downstream from canonical donor site and creates AG. MES scores: de novo variant = 5.2; canonical acceptor = 8.76. Ratio de novo variant/canonical acceptor = 5.2/8.76 = 0.59 --- it is below 0.8 Variant is not predicted to be damaging or alter splicing.
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Approved on: 2022-05-30
Published on: 2022-06-30
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