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.2448G>C (p.Lys816Asn)

CA404098878

440698 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: ee001706-6aa5-4f86-ae5c-073397ef9dd2

HGVS expressions

NM_000527.5:c.2448G>C

NM_000527.5(LDLR):c.2448G>C (p.Lys816Asn)

NC_000019.10:g.11129571G>C

CM000681.2:g.11129571G>C

NC_000019.9:g.11240247G>C

CM000681.1:g.11240247G>C

NC_000019.8:g.11101247G>C

NG_009060.1:g.45191G>C

ENST00000558518.6:c.2448G>C

ENST00000252444.9:n.2702G>C

ENST00000455727.6:c.1944G>C

ENST00000535915.5:c.2325G>C

ENST00000545707.5:c.1914G>C

ENST00000557933.5:c.2510G>C

ENST00000558013.5:c.2448G>C

ENST00000558518.5:c.2448G>C

ENST00000560628.1:n.108+1917G>C

NM_000527.4:c.2448G>C

NM_001195798.1:c.2448G>C

NM_001195799.1:c.2325G>C

NM_001195800.1:c.1944G>C

NM_001195803.1:c.1914G>C

NM_001195798.2:c.2448G>C

NM_001195799.2:c.2325G>C

NM_001195800.2:c.1944G>C

NM_001195803.2:c.1914G>C

Uncertain Significance

BP4 PM2

BA1 PP4 PP3 PVS1 BS1

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specification: ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.2

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

NM_000527.4(LDLR): c.2448G>C (p.Lys816Asn) variant is classified as Uncertain significance - insufficient evidence, for Familial Hypercholesterolemia by applying evidence codes PM2, 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 = 0.00006482 (0.007%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1). . BP4: REVEL = 0.5. It is not below 0.5, splicing evaluation is needed. Functional data on splicing not available. A) variant is not on limits B) Variant does not create GT or AG Variant is not predicted to affect splicing.

BP4

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

PM2

PopMax MAF = 0.00006482 (0.007%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1).

BA1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PP4

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PP3

REVEL = 0.5. It is not above 0.75, splicing evaluation needed. Functional data on splicing not available. A) variant is not on limits B) Variant does not create GT or AG C) There is an AG nearby. MES scores: wt cryptic = -4.18 Variant cryptic = 1.06 Canonical acceptor = 8,21. Variant is not predicted to affect splicing.

PVS1

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

Approved on: 2023-04-28

Published on: 2023-04-28

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