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]

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Variant: NM_000527.5(LDLR):c.1049G>A (p.Arg350Gln)

CA305299648

689349 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 201b657b-326b-45eb-aff5-29d04f0556fe

Approved on: 2023-04-28

Published on: 2023-04-28

HGVS expressions

NM_000527.5:c.1049G>A

NM_000527.5(LDLR):c.1049G>A (p.Arg350Gln)

NC_000019.10:g.11110760G>A

CM000681.2:g.11110760G>A

NC_000019.9:g.11221436G>A

CM000681.1:g.11221436G>A

NC_000019.8:g.11082436G>A

NG_009060.1:g.26380G>A

ENST00000558518.6:c.1049G>A

ENST00000252444.9:n.1303G>A

ENST00000455727.6:c.545G>A

ENST00000535915.5:c.926G>A

ENST00000545707.5:c.668G>A

ENST00000557933.5:c.1049G>A

ENST00000558013.5:c.1049G>A

ENST00000558518.5:c.1049G>A

ENST00000560173.1:n.48G>A

ENST00000560467.1:n.541-754G>A

NM_000527.4:c.1049G>A

NM_001195798.1:c.1049G>A

NM_001195799.1:c.926G>A

NM_001195800.1:c.545G>A

NM_001195803.1:c.668G>A

NM_001195798.2:c.1049G>A

NM_001195799.2:c.926G>A

NM_001195800.2:c.545G>A

NM_001195803.2:c.668G>A

Uncertain Significance

BS3 BP4 PP4 PM2

BS1 PS3 BA1 PP3

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_000527.5(LDLR):c.1049G>A (p.Arg350Gln) variant is classified as Uncertain significance - conflicting evidence, for Familial Hypercholesterolemia by applying evidence codes PM2, BP4, BS3 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 = 0.0001157 (0.01%) in Latino/Admixed Americans exomes+genomes (gnomAD v2.1.1). . BP4: REVEL = 0.373. it is below 0.50, so splicing evaluation is required. Functional data on splicing not available. A) Variant not on limits. B) Variant does not create GT. Variant is predicted not to alter splicing. . BS3: Level 1 assays: PMID 31106925 Heterologous cells (CHO), FACS assays - result - 100% LDLR expression, binding, and uptake . PP4: Variant meets PM2 and is identified in at least 1 index case with DLCN>=6/ from PMID 31106925, after alternative causes of high cholesterol were excluded.

BS3

Level 1 assays: PMID 31106925 Heterologous cells (CHO), FACS assays - result - 100% LDLR expression, binding, and uptake

BP4

REVEL = 0.373. it is below 0.50, so splicing evaluation is required. Functional data on splicing not available. A) Variant not on limits. B) Variant does not create GT. Variant is predicted not to alter splicing.

PP4

Variant meets PM2 and is identified in at least 1 index case with DLCN>=6/ from PMID 31106925, after alternative causes of high cholesterol were excluded.

PM2

PopMax MAF = 0.0001157 (0.01%) in Latino/Admixed Americans exomes+genomes (gnomAD v2.1.1).

BS1

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

BA1

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

PP3

REVEL = 0.373. It is not above 0.75, splicing evaluation needed. Functional data on splicing not available. A) Variant not on limits. B) Variant does not create GT. C) there is no GT nearby. Variant is predicted not to alter splicing.

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