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.1049G>C (p.Arg350Pro)

CA10576296

226343 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: baa65fd0-7621-400f-b358-8c8d1aaafcc5

HGVS expressions

NM_000527.5:c.1049G>C

NM_000527.5(LDLR):c.1049G>C (p.Arg350Pro)

NC_000019.10:g.11110760G>C

CM000681.2:g.11110760G>C

NC_000019.9:g.11221436G>C

CM000681.1:g.11221436G>C

NC_000019.8:g.11082436G>C

NG_009060.1:g.26380G>C

ENST00000558518.6:c.1049G>C

ENST00000252444.9:n.1303G>C

ENST00000455727.6:c.545G>C

ENST00000535915.5:c.926G>C

ENST00000545707.5:c.668G>C

ENST00000557933.5:c.1049G>C

ENST00000558013.5:c.1049G>C

ENST00000558518.5:c.1049G>C

ENST00000560173.1:n.48G>C

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

NM_000527.4:c.1049G>C

NM_001195798.1:c.1049G>C

NM_001195799.1:c.926G>C

NM_001195800.1:c.545G>C

NM_001195803.1:c.668G>C

NM_001195798.2:c.1049G>C

NM_001195799.2:c.926G>C

NM_001195800.2:c.545G>C

NM_001195803.2:c.668G>C

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

PP4 PS4_Supporting PM2 PS3_Moderate PP1_Moderate

PP3 PM1 PVS1 BA1 BS4 BS3 BS1 BP4

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.1049G>C (p.Arg350Pro) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PS4_Supporting, PP1_Moderate, PP4, and PS3 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: This variant is absent from gnomAD (gnomAD v2.1.1). . PS4_Supporting: Variant meets PM2 and is identified in 5 index cases: 4 cases with DLCN criteria>=6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA), 1 case with DLCN criteria>=6 in Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France . PP1_Moderate: Variant segregates with FH phenotype in 5 informative meioses in 3 families from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA). 3 relatives without the phenotype and the variant, 2 relatives with the phenotype and the variant . PP4: Variant meets PM2 and is identified in at least 1 index case with DLCN>=6 after alternative causes of high cholesterol were excluded. Data is from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) and Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France. . PS3_moderate: Level 2 assays: PMID 15100232 Heterologous cells (CHO) ACS, WB and NMR Spectroscopy <10% cell surface LDLR, 65% binding, (WB), ~10% expression

PP4

Variant meets PM2 and is identified in at least 1 index case with DLCN>=6 after alternative causes of high cholesterol were excluded. Data is from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) and Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France.

PS4_Supporting

Variant meets PM2 and is identified in 5 index cases: 4 cases with DLCN criteria>=6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA), 1 case with DLCN criteria>=6 in Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France

PM2

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

PS3_Moderate

Level 2 assays: PMID 15100232 Heterologous cells (CHO) ACS, WB and NMR Spectroscopy <10% cell surface LDLR, 65% binding, (WB), ~10% expression

PP1_Moderate

Variant segregates with FH phenotype in 5 informative meioses in 3 families from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA). 3 relatives without the phenotype and the variant, 2 relatives with the phenotype and the variant

PP3

REVEL = 0.648. 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 to alter splicing.

PM1

Variant no on Exon 4

PVS1

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

BA1

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

BS4

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

BS3

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

BS1

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

BP4

Approved on: 2023-04-28

Published on: 2023-04-28

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.