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

CA023654

161286 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: 4c3500b5-196e-41cb-9c85-e39a63577757

Approved on: 2022-05-30

Published on: 2022-06-30

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: PM2 PS4_Supporting PP4

• Not Met criteria codes: PM6 PM3 PM1 PM4 PM5 PVS1 BS2 BS4 BS3 BS1 BP5 BP7 BP2 BP3 BP4 BP1 PS2 PS3 PS1 PP1 PP3 PP2 BA1

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

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

• 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.
• PVS1: 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
• 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
• 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
• 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
• 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
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline