Variant: NM_000527.5(LDLR):c.1721G>A (p.Arg574His)

CA036197

251996 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: 4eae98db-aaea-4688-83be-718337c06f12

Approved on: 2022-02-13

Published on: 2022-07-12

HGVS expressions

NM_000527.5:c.1721G>A
NM_000527.5(LDLR):c.1721G>A (p.Arg574His)
NC_000019.10:g.11116874G>A
CM000681.2:g.11116874G>A
NC_000019.9:g.11227550G>A
CM000681.1:g.11227550G>A
NC_000019.8:g.11088550G>A
NG_009060.1:g.32494G>A
ENST00000558518.6:c.1721G>A
ENST00000252444.9:n.1975G>A
ENST00000455727.6:c.1217G>A
ENST00000535915.5:c.1598G>A
ENST00000545707.5:c.1340G>A
ENST00000557933.5:c.1721G>A
ENST00000558013.5:c.1721G>A
ENST00000558518.5:c.1721G>A
ENST00000559340.1:n.426+662G>A
NM_000527.4:c.1721G>A
NM_001195798.1:c.1721G>A
NM_001195799.1:c.1598G>A
NM_001195800.1:c.1217G>A
NM_001195803.1:c.1340G>A
NM_001195798.2:c.1721G>A
NM_001195799.2:c.1598G>A
NM_001195800.2:c.1217G>A
NM_001195803.2:c.1340G>A

Likely Pathogenic

• Met criteria codes: PP4 PP3 PM2 PP1_Strong

• Not Met criteria codes: BA1 BP2 BP3 BP4 BP1 BP5 BP7 BS2 BS4 BS3 BS1 PVS1 PP2 PM6 PM3 PM1 PM4 PM5 PS2 PS4 PS3 PS1

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>A (p.Arg574His) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PP1_strong, PM2, PP3 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: PP1_strong - PMID: 20018285 - 6 informative meioses in 1 family. PM2 - PopMax MAF = 0.0001129 (0.01129%) in Latino exomes+genomes (gnomAD v2.1.1). PP3 - REVEL = 0.971. PP4 - Variant meets PM2. PMID: 20018285 - 1 case with DLCN > 6.

Met criteria codes

• PP4: Variant meets PM2. PMID: 20018285 - 1 case with DLCN > 6.
• PP3: REVEL = 0.971
• PM2: PopMax MAF = 0.0001129 (0.01129%) in Latino exomes+genomes (gnomAD v2.1.1).
• PP1_Strong: PMID: 20018285 - 6 informative meioses in 1 family

Not Met criteria codes

• BA1: 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
• 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
• 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
• PVS1: 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
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• 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>T (p.Arg574Leu) (ClinVar ID 237867) - Uncertain significance by these guidelines There is no variant in the same codon classified as Pathogenic by these guidelines.
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: 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