Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

Variant: NM_000527.5(LDLR):c.1816G>A (p.Ala606Thr)

CA036744

252046 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 68b76ea3-2708-45f4-ad77-372980b3d08c

HGVS expressions

NM_000527.5:c.1816G>A

NM_000527.5(LDLR):c.1816G>A (p.Ala606Thr)

NC_000019.10:g.11116969G>A

CM000681.2:g.11116969G>A

NC_000019.9:g.11227645G>A

CM000681.1:g.11227645G>A

NC_000019.8:g.11088645G>A

NG_009060.1:g.32589G>A

ENST00000558518.6:c.1816G>A

ENST00000252444.9:n.2070G>A

ENST00000455727.6:c.1312G>A

ENST00000535915.5:c.1693G>A

ENST00000545707.5:c.1435G>A

ENST00000557933.5:c.1816G>A

ENST00000558013.5:c.1816G>A

ENST00000558518.5:c.1816G>A

ENST00000559340.1:n.426+757G>A

NM_000527.4:c.1816G>A

NM_001195798.1:c.1816G>A

NM_001195799.1:c.1693G>A

NM_001195800.1:c.1312G>A

NM_001195803.1:c.1435G>A

NM_001195798.2:c.1816G>A

NM_001195799.2:c.1693G>A

NM_001195800.2:c.1312G>A

NM_001195803.2:c.1435G>A

Uncertain Significance

The Expert Panel has overridden the computationally generated classification - "[unknown]"

BP4 PS4 PP4 PP3 PM5 PM2

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5 (LDLR): c. 1816G>A (p.Ala606Thr) variant is classified as Uncertain significance -insufficient evidence for Familial Hypercholesterolemia as no evidence codes were met 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 not Met: PopMax MAF = 0.0002024 in Latino population in gnomAD (gnomAD v2.1.1), and PopMAX MAF = 0.00043 in Latino population in ExAC (ExAC v0.3.1). PP3 not Met: REVEL = 0.725, which is below 0.75. Functional data on splicing is not available, in silico splicing prediction is required. The variant is exonic and located at least 50 bases downstream of authentic acceptor site, but it does not create GT. The variant is not on limit creating de novo acceptor site. Therefore, this variant is not predicted to alter splicing. BP4 not applicable: REVEL score for this variant is not below 0.5, BP4 is not applicable. PP4, PS4 not applicable: Variant did not meet PM2. PM5 not met: There are two other variants in same codon: LDLR: NM_000527:c1816G>T (p.Ala606Ser), LDLR: NM_000527:c.1817C>A (p.Ala606Asp), which are classified as Uncertain significance by these guidelines. Therefore PM5 is not met.

BP4

REVEL score for this variant is not below 0.5, BP4 is not applicable.

PS4

Variant did not meet PM2.

PP4

Variant did not meet PM2.

PP3

REVEL = 0.725, which is below 0.75. Functional data on splicing is not available, in silico splicing prediction is required. The variant is exonic and located at least 50 bases downstream of authentic acceptor site, but it does not create GT. The variant is not on limit creating de novo acceptor site. Therefore, this variant is not predicted to alter splicing.

PM5

There are two other variants in same codon: LDLR: NM_000527:c1816G>T (p.Ala606Ser), LDLR: NM_000527:c.1817C>A (p.Ala606Asp), which are classified as Uncertain significance by these guidelines. Therefore PM5 is not met.

PM2

PopMax MAF = 0.0002024 in Latino population in gnomAD (gnomAD v2.1.1), and PopMAX MAF = 0.00043 in Latino population in ExAC (ExAC v0.3.1).FAF = 0.00043 in Latino population in ExAC (Version 0.3.1).

Approved on: 2022-05-08

Published on: 2022-12-24

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