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]

Variant: NM_000527.5(LDLR):c.1867A>G (p.Ile623Val)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA037254

252096 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 71c55d4d-b913-48cb-bb50-fdfa27e456bc

Approved on: 2023-01-27

Published on: 2024-09-25

HGVS expressions

NM_000527.5:c.1867A>G

NM_000527.5(LDLR):c.1867A>G (p.Ile623Val)

NC_000019.10:g.11120113A>G

CM000681.2:g.11120113A>G

NC_000019.9:g.11230789A>G

CM000681.1:g.11230789A>G

NC_000019.8:g.11091789A>G

NG_009060.1:g.35733A>G

ENST00000252444.10:c.2125A>G

ENST00000559340.2:c.1727A>G

ENST00000560467.2:c.1747A>G

ENST00000558518.6:c.1867A>G

ENST00000252444.9:c.2121A>G

ENST00000455727.6:c.1363A>G

ENST00000535915.5:c.1744A>G

ENST00000545707.5:c.1486A>G

ENST00000557933.5:c.1867A>G

ENST00000558013.5:c.1867A>G

ENST00000558518.5:c.1867A>G

ENST00000559340.1:c.448A>G

NM_000527.4:c.1867A>G

NM_001195798.1:c.1867A>G

NM_001195799.1:c.1744A>G

NM_001195800.1:c.1363A>G

NM_001195803.1:c.1486A>G

NM_001195798.2:c.1867A>G

NM_001195799.2:c.1744A>G

NM_001195800.2:c.1363A>G

NM_001195803.2:c.1486A>G

Uncertain Significance

PP1 BS1

BA1 PP4 PVS1 PM5 PM3 PM1 PM4 PM6 PM2 BS2 BS4 BS3 BP2 BP3 BP4 PS1 PS2 PS3

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.1867A>G (p.Ile623Val) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes BS1 and PP1 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 27 January 2023. The supporting evidence is as follows: The supporting evidence is as follows: BS1: PopMax FAF= 0.002650 (0.265%) in East Asian exomes (gnomAD v2.1.1). PP1: Variant segregates with FH phenotype in 2 informative meioses in 1 family from Laboratory of Genetics and Molecular Cardiology, Brazil.

PP1

Variant segregates with FH phenotype in 2 informative meioses in 1 family from Laboratory of Genetics and Molecular Cardiology. So PP1 is met.

BS1

PopMax FAF= 0.002650 (0.265%) in East Asian exomes (gnomAD v2.1.1). So BS1 is met.

BA1

PopMax FAF= 0.002650 (0.265%) in East Asian exomes (gnomAD v2.1.1)

PP4

Variant doesn't meet PM2.

PVS1

Not a null variant

PM5

1 other missense variant in the same codon: - NM_000527.5(LDLR):c.1868T>C (p.Ile623Thr) (ClinVar ID 369855) - Unknown significance by these guidelines There is no variant in the same codon classified as Pathogenic by these guidelines.

PM3

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

PM1

Not in exon 4. Not a cysteine residue.

PM4

No in-frame deletions/insertions

PM6

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

PM2

PopMax MAF= 0.00356 (0.356%) in East Asians (gnomAD v2.1.1)

BS2

Variant identified in 2 normolipidemic, untreated, unrelated adults from PMID 12837857

BS4

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

BS3

No data available

BP2

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

BP3

No in-frame deletions/insertions

BP4

REVEL=0.742. It is above 0.5.

PS1

No other missense variant in the same codon with the same amino acid change.

PS2

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

PS3

No data available

Curation History

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