Variant: NM_000527.5(LDLR):c.1721G>T (p.Arg574Leu)

CA036228

237867 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: 68efc539-d28f-4ac9-8921-fffe416b1827

Approved on: 2022-03-30

Published on: 2022-07-12

HGVS expressions

NM_000527.5:c.1721G>T
NM_000527.5(LDLR):c.1721G>T (p.Arg574Leu)
NC_000019.10:g.11116874G>T
CM000681.2:g.11116874G>T
NC_000019.9:g.11227550G>T
CM000681.1:g.11227550G>T
NC_000019.8:g.11088550G>T
NG_009060.1:g.32494G>T
ENST00000558518.6:c.1721G>T
ENST00000252444.9:n.1975G>T
ENST00000455727.6:c.1217G>T
ENST00000535915.5:c.1598G>T
ENST00000545707.5:c.1340G>T
ENST00000557933.5:c.1721G>T
ENST00000558013.5:c.1721G>T
ENST00000558518.5:c.1721G>T
ENST00000559340.1:n.426+662G>T
NM_000527.4:c.1721G>T
NM_001195798.1:c.1721G>T
NM_001195799.1:c.1598G>T
NM_001195800.1:c.1217G>T
NM_001195803.1:c.1340G>T
NM_001195798.2:c.1721G>T
NM_001195799.2:c.1598G>T
NM_001195800.2:c.1217G>T
NM_001195803.2:c.1340G>T

Uncertain Significance

• Met criteria codes: PM2 PS4_Supporting PP4 PP3

• Not Met criteria codes: PM3 PM1 PM4 PM5 PM6 PVS1 BS2 BS4 BS3 BS1 BP5 BP7 BP2 BP3 BP4 BP1 PS2 PS3 PS1 PP1 PP2 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 1.1

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

NM_000527.5(LDLR):c.1721G>T (p.Arg574Leu) variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PS4_supporting 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 = 0.0001848 (0.01848%) in European (Finnish) exomes+genomes (gnomAD v2.1.1). PP3 - REVEL = 0.937. PP4 - Variant meets PM2. Identified in 2 FH case from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) with clinical Simon Broome score possible/definite, after alternative causes of high cholesterol were excluded. PS4_supporting - Variant meets PM2. Variant identified in 2 index cases Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) with Simon Broome criteria (possible/definite).

Met criteria codes

• PM2: PopMax MAF = 0.0001848 (0.01848%) in European (Finnish) exomes+genomes (gnomAD v2.1.1).
• PS4_Supporting: Variant meets PM2. Variant identified in 2 index cases Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) with Simon Broome criteria (possible/definite).
• PP4: Variant meets PM2. Identified in 2 FH case from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) with clinical Simon Broome score possible/definite, after alternative causes of high cholesterol were excluded.
• PP3: REVEL = 0,937

Not Met criteria codes

• PM3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: 2 other missense variants in the same codon: - NM_000527.5(LDLR):c.1720C>T (p.Arg574Cys) (ClinVar ID 183123) - Uncertain significance by these guidelines - NM_000527.5(LDLR):c.1721G>A (p.Arg574His) (ClinVar ID 251996) - Likely pathogenic by these guidelines There is no variant in the same codon classified as Pathogenic by these guidelines.
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PVS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS2: 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: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP7: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS2: 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
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP2: 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