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.758G>C (p.Arg253Pro)

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CA10585115

251435 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 5204a9d1-8c95-466b-b752-b6013d992ee4

Approved on: 2022-04-22

Published on: 2022-04-22

HGVS expressions

NM_000527.5:c.758G>C

NM_000527.5(LDLR):c.758G>C (p.Arg253Pro)

NC_000019.10:g.11106628G>C

CM000681.2:g.11106628G>C

NC_000019.9:g.11217304G>C

CM000681.1:g.11217304G>C

NC_000019.8:g.11078304G>C

NG_009060.1:g.22248G>C

ENST00000558518.6:c.758G>C

ENST00000252444.9:n.1012G>C

ENST00000455727.6:c.314-764G>C

ENST00000535915.5:c.635G>C

ENST00000545707.5:c.377G>C

ENST00000557933.5:c.758G>C

ENST00000558013.5:c.758G>C

ENST00000558518.5:c.758G>C

ENST00000558528.1:n.273G>C

ENST00000560467.1:n.358G>C

NM_000527.4:c.758G>C

NM_001195798.1:c.758G>C

NM_001195799.1:c.635G>C

NM_001195800.1:c.314-764G>C

NM_001195803.1:c.377G>C

NM_001195798.2:c.758G>C

NM_001195799.2:c.635G>C

NM_001195800.2:c.314-764G>C

NM_001195803.2:c.377G>C

Uncertain Significance

PP4 PP3 PM2

BS3 BS1 BS2 BP7 BP4 PS4 PS3 PS1 BA1 PM4 PM1 PM5 PVS1

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.758G>C (p.Arg253Pro) variant is classified as Uncertain significance – insufficient evidence for Familial Hypercholesterolemia by applying evidence PM2, PP3, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (v2.1.1). PP3 - REVEL = 0.77, which is above the threshold of 0.75. PP4 - Variant meets PM2 and was identified in 1 index case with Simon Broome criteria for FH (PMID: 20236128) after alternative causes of cholesterol were excluded. Note: two other missense variants at this same codon have been reported: 1) NM_000527.5(LDLR):c.757C>T (p.Arg253Trp); 2) NM_000527.5(LDLR):c.758G>A (p.Arg253Gln); however, both are VUS by these LDLR guidelines (PM5 not applicable).

PP4

Variant meets PM2 and is identified in one index case who fulfils SB criteria for FH from PMID: 20236128, after alternative causes of high cholesterol were excluded.

PP3

REVEL = 0.77; score is above 0.75 threshold.

PM2

This variant is absent from gnomAD (gnomAD v2.1.1).

BS3