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.1792A>C (p.Ile598Leu)

CA10585613

252032 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: adab973c-c0e5-4f1d-ab9b-0a7a99fb9733
Approved on: 2023-04-28
Published on: 2023-05-01

HGVS expressions

NM_000527.5:c.1792A>C
NM_000527.5(LDLR):c.1792A>C (p.Ile598Leu)
NC_000019.10:g.11116945A>C
CM000681.2:g.11116945A>C
NC_000019.9:g.11227621A>C
CM000681.1:g.11227621A>C
NC_000019.8:g.11088621A>C
NG_009060.1:g.32565A>C
ENST00000558518.6:c.1792A>C
ENST00000252444.9:n.2046A>C
ENST00000455727.6:c.1288A>C
ENST00000535915.5:c.1669A>C
ENST00000545707.5:c.1411A>C
ENST00000557933.5:c.1792A>C
ENST00000558013.5:c.1792A>C
ENST00000558518.5:c.1792A>C
ENST00000559340.1:n.426+733A>C
NM_000527.4:c.1792A>C
NM_001195798.1:c.1792A>C
NM_001195799.1:c.1669A>C
NM_001195800.1:c.1288A>C
NM_001195803.1:c.1411A>C
NM_001195798.2:c.1792A>C
NM_001195799.2:c.1669A>C
NM_001195800.2:c.1288A>C
NM_001195803.2:c.1411A>C

Uncertain Significance

Met criteria codes 3
BP4 PP4 PM2
Not Met criteria codes 23
BA1 BP2 BP3 BP1 BP5 BP7 BS2 BS4 BS3 BS1 PVS1 PP1 PP3 PP2 PM6 PM3 PM1 PM4 PM5 PS2 PS4 PS3 PS1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.2

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
The NM_000527.5(LDLR):c.1792A>C (p.Ile598Leu) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4 and BP4) 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). PP4 - Variant meet PM2. PMID: 11810272 (Fouchier et al., 2001), Netherlands - et least 1 case who fulfills validated clinical criteria for FH. BP4 - REVEL: 0.487, it is below 0.50, splicing evaluation required. Functional data on splicing not available. Scenario A, Acceptor site: The variant is not located at -20 to +3 bases of canonical acceptor splicing site of any exons. Scenario A, Donor site: The variant is not located at -3 to +6 bases of canonical splicing site of any exons. Scenario B, Acceptor site: The variant is located within the range but does not create de novo AG site. Scenario B, Donor site: The variant is located within range but does not create de novo GT site. Scenario C, Acceptor site: The variant is located at -20 to +3 bases of intraexonic AG but AG is not within the range. Scenario C, Donor site: The variant is not located at -3 to +6 bases of intraexonic GT Interpretation: The variant does not affect splicing.
Met criteria codes
BP4
REVEL: 0.487, it is below 0.50, splicing evaluation required. Functional data on splicing not available. Scenario A, Acceptor site: The variant is not located at -20 to +3 bases of canonical acceptor splicing site of any exons. Scenario A, Donor site: The variant is not located at -3 to +6 bases of canonical splicing site of any exons. Scenario B, Acceptor site: The variant is located within the range but does not create de novo AG site. Scenario B, Donor site: The variant is located within range but does not create de novo GT site. Scenario C, Acceptor site: The variant is located at -20 to +3 bases of intraexonic AG but AG is not within the range. Scenario C, Donor site: The variant is not located at -3 to +6 bases of intraexonic GT Interpretation: The variant does not affect splicing
PP4
Variant meet PM2. PMID: 11810272 (Fouchier et al., 2001), Netherlands - et least 1 case who fulfills validated clinical criteria for FH.
PM2
This variant is absent from gnomAD (gnomAD v2.1.1).
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
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
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
REVEL: 0.487
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.1793T>A (p.Ile598Asn).(ClinVar ID 252033) - Uncertain significance - insufficient evidence by these guidelines - NM_000527.5(LDLR):c.1793T>C (p.Ile598Thr) (ClinVar ID 252034) - Uncertain significance - insufficient evidence 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
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