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]

Variant: NM_000527.5(LDLR):c.2126G>A (p.Arg709Lys)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA023641

183132 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 881f0b90-6bad-48a9-8769-6b78bdc81962

Approved on: 2024-10-28

Published on: 2025-01-19

HGVS expressions

NM_000527.5:c.2126G>A

NM_000527.5(LDLR):c.2126G>A (p.Arg709Lys)

NC_000019.10:g.11120508G>A

CM000681.2:g.11120508G>A

NC_000019.9:g.11231184G>A

CM000681.1:g.11231184G>A

NC_000019.8:g.11092184G>A

NG_009060.1:g.36128G>A

ENST00000252444.10:c.2384G>A

ENST00000559340.2:c.*195G>A

ENST00000560467.2:c.2006G>A

ENST00000558518.6:c.2126G>A

ENST00000252444.9:c.2380G>A

ENST00000455727.6:c.1622G>A

ENST00000535915.5:c.2003G>A

ENST00000545707.5:c.1606+275G>A

ENST00000557933.5:c.2126G>A

ENST00000558013.5:c.2126G>A

ENST00000558518.5:c.2126G>A

NM_000527.4:c.2126G>A

NM_001195798.1:c.2126G>A

NM_001195799.1:c.2003G>A

NM_001195800.1:c.1622G>A

NM_001195803.1:c.1606+275G>A

NM_001195798.2:c.2126G>A

NM_001195799.2:c.2003G>A

NM_001195800.2:c.1622G>A

NM_001195803.2:c.1606+275G>A

Uncertain Significance

PP3 PM2

PS3 PS4 PP4 PM5 BS3

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

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5 (LDLR):c.2126G>A (p.Arg709Lys) variant is classified as Uncertain significance – insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 October 2024. The supporting evidence is as follows: PM2: PopMax MAF=0.000003390 in non-Finnish European exomes+genomes (gnomAD v4.1.0). PP3: REVEL=0.842.

PP3

REVEL=0.842, which is above impact threshold.

PM2

PopMaxMAF=0.000003390 in non-Finnish European exomes+genomes (gnomAD v4.1.0).

PS3

Functional data is not available.

PS4

Clinical data is not available.

PP4

Clinical data is not available.

PM5

One other variant in the same codon: NM_000527.5 (LDLR):c. 2125A>G (p.Arg709Gly)(ClinVarID 375833) is classified as VUS by these guidelines. Therefore, PM5 is not met.

BS3

BS3_Supporting not met – In vitro microscopy assays in HeLa cells shown LDLR activity similar to WT - considered as non-disruptive, reported by Thormaehlen et al, 2015 in PMID2564724, from University of Heidelberg, Germany. However, it has been decided by FH VCEP that the results from PMID2564724 are ok to be used towards PS3_Supporting, but not towards BS3_Supporting, because the functional study from this report did not look at the whole LDLR cycle.

Curation History

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