Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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Variant: NM_000527.5(LDLR):c.1721G>A (p.Arg574His)

CA036197

251996 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 4eae98db-aaea-4688-83be-718337c06f12

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 4
PP4 PP3 PP1_Strong PM2
Not Met criteria codes 22
BS4 BS3 BS1 BS2 BP5 BP7 BP2 BP3 BP4 BP1 PVS1 PS2 PS4 PS3 PS1 PP2 PM6 PM3 PM1 PM4 PM5 BA1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.1

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
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
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).
Not Met criteria codes
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
BS2
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
PVS1
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
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
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.
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Approved on: 2022-02-13
Published on: 2022-07-12
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