Variant: NM_000527.5(LDLR):c.1503G>A (p.Ala501=)

CA034586

251876 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: 7eefa188-b416-4524-a682-6645dee9f628

Approved on: 2022-08-27

Published on: 2022-12-23

HGVS expressions

NM_000527.5:c.1503G>A
NM_000527.5(LDLR):c.1503G>A (p.Ala501=)
NC_000019.10:g.11113679G>A
CM000681.2:g.11113679G>A
NC_000019.9:g.11224355G>A
CM000681.1:g.11224355G>A
NC_000019.8:g.11085355G>A
NG_009060.1:g.29299G>A
ENST00000558518.6:c.1503G>A
ENST00000252444.9:n.1757G>A
ENST00000455727.6:c.999G>A
ENST00000535915.5:c.1380G>A
ENST00000545707.5:c.1122G>A
ENST00000557933.5:c.1503G>A
ENST00000558013.5:c.1503G>A
ENST00000558518.5:c.1503G>A
ENST00000559340.1:n.224G>A
NM_000527.4:c.1503G>A
NM_001195798.1:c.1503G>A
NM_001195799.1:c.1380G>A
NM_001195800.1:c.999G>A
NM_001195803.1:c.1122G>A
NM_001195798.2:c.1503G>A
NM_001195799.2:c.1380G>A
NM_001195800.2:c.999G>A
NM_001195803.2:c.1122G>A

Uncertain Significance

• Met criteria codes: PP3 PM2

• Not Met criteria codes: PS4 PP4

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.1503G>A (p.Ala501=) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3) 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 = 0.0002403 (0.02403%) in African/African American population exomes/genomes (gnomAD version). PP3: No REVEL score, splicing evaluation required. Functional data on splicing not available. B). Variant is exonic and at least 50bp upstream from canonical donor site and creates AG MES scores: de novo variant = 9.20; canonical acceptor = 6.76. Ratio de novo variant/canonical acceptor = 9.20/6.76 = 1.36 --- it is above 0.9 PP4: variant meets PM2, identified in 1 FH index case from PMID: 20145306 with WHO criteria, after alternative causes of high cholesterol were excluded.

Met criteria codes

• PP3: No REVEL score, splicing evaluation required. Functional data on splicing not available. B). Variant is exonic and at least 50bp upstream from canonical donor site and creates AG MES scores: de novo variant = 9.20; canonical acceptor = 6.76. Ratio de novo variant/canonical acceptor = 9.20/6.76 = 1.36 --- it is above 0.9 Variant is predicted to alter splicing.
• PM2: PopMax MAF = 0.0002403 (0.02403%) in African/African American population exomes/genomes (gnomAD v2.1.1).

Not Met criteria codes

• PS4: Variant only identified in 1 index case from Ambry Genetics with no clinical data. From literature search, in PMID: 20145306, variant identified in 1 index with WHO criteria, could count. However, only 1 index case overall, so PS4 not met.
• PP4: variant meets PM2, identified in 1 FH index case from PMID: 20145306 with WHO criteria, however, standard not specified, so not MET.