Variant: NM_000527.5(LDLR):c.1765G>A (p.Asp589Asn)

CA036508

252022 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: fd0cb6c9-7f1e-4644-9c34-95083a79a553

Approved on: 2022-08-29

Published on: 2022-12-23

HGVS expressions

NM_000527.5:c.1765G>A
NM_000527.5(LDLR):c.1765G>A (p.Asp589Asn)
NC_000019.10:g.11116918G>A
CM000681.2:g.11116918G>A
NC_000019.9:g.11227594G>A
CM000681.1:g.11227594G>A
NC_000019.8:g.11088594G>A
NG_009060.1:g.32538G>A
ENST00000558518.6:c.1765G>A
ENST00000252444.9:n.2019G>A
ENST00000455727.6:c.1261G>A
ENST00000535915.5:c.1642G>A
ENST00000545707.5:c.1384G>A
ENST00000557933.5:c.1765G>A
ENST00000558013.5:c.1765G>A
ENST00000558518.5:c.1765G>A
ENST00000559340.1:n.426+706G>A
NM_000527.4:c.1765G>A
NM_001195798.1:c.1765G>A
NM_001195799.1:c.1642G>A
NM_001195800.1:c.1261G>A
NM_001195803.1:c.1384G>A
NM_001195798.2:c.1765G>A
NM_001195799.2:c.1642G>A
NM_001195800.2:c.1261G>A
NM_001195803.2:c.1384G>A

Uncertain Significance

• Met criteria codes: BP4

• Not Met criteria codes: BP5 PM2 PM5 PS4

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.1765G>A (p.Asp589Asn) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes 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: BP4 - REVEL = 0.325. It is below 0.5, splicing evaluation needed. Functional data on splicing not available. A) variant not on limits. B) does not create AG or GT Variant is not predicted to alter splicing

Met criteria codes

• BP4: BP4 - REVEL = 0.325. It is below 0.5, splicing evaluation needed. Functional data on splicing not available. A) variant not on limits. B) does not create AG or GT Variant is not predicted to alter splicing

Not Met criteria codes

• BP5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM2: PM2 - PopMax MAF = 0.001053 (0.11%) in East-Asian European exomes/genomes (gnomAD v2.1.1).
• PM5: 2 other variants in the same codon but both are classified as VUS per ClinGen LDLR VCEP guidelines
• PS4: MAF = 0.105% in East Asians