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]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_000527.5(LDLR):c.292G>C (p.Gly98Arg)

CA10584830

251119 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: ed01a933-88a1-4711-903f-8c86286a34f8
Approved on: 2024-02-23
Published on: 2024-12-02

HGVS expressions

NM_000527.5:c.292G>C
NM_000527.5(LDLR):c.292G>C (p.Gly98Arg)
NC_000019.10:g.11102765G>C
CM000681.2:g.11102765G>C
NC_000019.9:g.11213441G>C
CM000681.1:g.11213441G>C
NC_000019.8:g.11074441G>C
NG_009060.1:g.18385G>C
ENST00000252444.10:c.550G>C
ENST00000559340.2:c.292G>C
ENST00000560467.2:c.292G>C
ENST00000558518.6:c.292G>C
ENST00000252444.9:c.546G>C
ENST00000455727.6:c.292G>C
ENST00000535915.5:c.190+2420G>C
ENST00000545707.5:c.292G>C
ENST00000557933.5:c.292G>C
ENST00000557958.1:n.378G>C
ENST00000558013.5:c.292G>C
ENST00000558518.5:c.292G>C
NM_000527.4:c.292G>C
NM_001195798.1:c.292G>C
NM_001195799.1:c.190+2420G>C
NM_001195800.1:c.292G>C
NM_001195803.1:c.292G>C
NM_001195798.2:c.292G>C
NM_001195799.2:c.190+2420G>C
NM_001195800.2:c.292G>C
NM_001195803.2:c.292G>C
More

Uncertain Significance

Met criteria codes 2
PP4 PM2
Not Met criteria codes 19
PVS1 BA1 BS2 BS4 BS3 BS1 BP3 BP2 BP4 BP7 PS4 PS3 PS1 PP1 PP3 PM1 PM4 PM3 PM5

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

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
The NM_000527.5(LDLR):c.292G>C (p.Gly98Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PP4: Variant meets PM2 and is identified in 1 case with possible FH by Simon Broome criteria from Cardiovascular Research Group, Instituto Nacional de Saúde Doutor Ricardo Jorge, Portugal, after alternative causes of high cholesterol were excluded.
Met criteria codes
PP4
Variant meets PM2. Identified in 1 FH case from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, fulfilling criteria for possible FH using SB criteria, after alternative causes of high cholesterol were excluded.
PM2
This variant is absent from gnomAD (gnomAD v2.1.1).
Not Met criteria codes
PVS1
Not applicable
BA1
This variant is absent from gnomAD (gnomAD v2.1.1).
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No family members were tested
BS3
Level 1 assays: PMID 35568682 - Heterologous cells (CHO), FACS assays - Result: 84% cell surface LDLR, 87% LDL-LDLR binding and 82% internalization (Not above 90%) ---- functional study is not consistent with no damaging effect.
BS1
This variant is absent from gnomAD (gnomAD v2.1.1).
BP3
Not applicable
BP2
No other variants were identified in the index case
BP4
REVEL = 0.68, it is not below 0.5
BP7
Not applicable
PS4
Variant is found in only 1 Index case
PS3
Level 1 assays: PMID 35568682 - Heterologous cells (CHO), FACS assays - Result: 84% cell surface LDLR, 87% LDL-LDLR binding and 82% internalization (Not below 70%) ---- functional study is not consistent with damaging effect.
PS1
3 other missense variants in the same codon: NM_000527.5(LDLR):c.292G>T (p.Gly98Cys) (ClinVar ID 889190): - Uncertain significance by these guidelines NM_000527.5(LDLR):c.292G>A (p.Gly98Ser) (ClinVar ID 251118) - Conflicting classifications of pathogenicity by these guidelines NM_000527.5(LDLR):c.293G>C (p.Gly98Ala) (ClinVar ID 920443) - Uncertain significance by these guidelines There are no variants in the same codon classified as Pathogenic by these guidelines
PP1
No family members were tested
PP3
REVEL = 0.68, it is below 0.7. Splicing evaluation needed. Functional data on splicing is unavailable A) Variant not on limits. B) Variant does not create GT. C) There is no GT nearby Variant is not predicted to alter splicing.
PM1
Not applicable
PM4
Not applicable
PM3
No other variants were identified in the index case
PM5
3 other missense variants in the same codon: NM_000527.5(LDLR):c.292G>T (p.Gly98Cys) (ClinVar ID 889190): - Uncertain significance by these guidelines NM_000527.5(LDLR):c.292G>A (p.Gly98Ser) (ClinVar ID 251118) - Conflicting classifications of pathogenicity by these guidelines NM_000527.5(LDLR):c.293G>C (p.Gly98Ala) (ClinVar ID 920443) - Uncertain significance by these guidelines There are no variants in the same codon classified as Pathogenic by these guidelines
Curation History
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