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

CA10576296

226343 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

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

Approved on: 2023-04-28

Published on: 2023-04-28

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"

• Met criteria codes: PM2 PS4_Supporting PS3_Moderate PP1_Moderate PP4

• Not Met criteria codes: PM1 PVS1 BS4 BS3 BS1 BP4 PP3 BA1

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

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

Met criteria codes

• 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
• 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
• 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.

Not Met criteria codes

• 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
• 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: 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.
• 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.
• BA1: This variant is absent from gnomAD (gnomAD v2.1.1).