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>A (p.Gly98Ser)

CA042749

251118 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: ff7318d7-47d1-4366-820f-4af2d1965a2f
Approved on: 2024-02-23
Published on: 2024-12-02

HGVS expressions

NM_000527.5:c.292G>A
NM_000527.5(LDLR):c.292G>A (p.Gly98Ser)
NC_000019.10:g.11102765G>A
CM000681.2:g.11102765G>A
NC_000019.9:g.11213441G>A
CM000681.1:g.11213441G>A
NC_000019.8:g.11074441G>A
NG_009060.1:g.18385G>A
ENST00000252444.10:c.550G>A
ENST00000559340.2:c.292G>A
ENST00000560467.2:c.292G>A
ENST00000558518.6:c.292G>A
ENST00000252444.9:c.546G>A
ENST00000455727.6:c.292G>A
ENST00000535915.5:c.190+2420G>A
ENST00000545707.5:c.292G>A
ENST00000557933.5:c.292G>A
ENST00000557958.1:n.378G>A
ENST00000558013.5:c.292G>A
ENST00000558518.5:c.292G>A
NM_000527.4:c.292G>A
NM_001195798.1:c.292G>A
NM_001195799.1:c.190+2420G>A
NM_001195800.1:c.292G>A
NM_001195803.1:c.292G>A
NM_001195798.2:c.292G>A
NM_001195799.2:c.190+2420G>A
NM_001195800.2:c.292G>A
NM_001195803.2:c.292G>A
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Uncertain Significance

Met criteria codes 1
BS3
Not Met criteria codes 8
PM5 PM2 BS1 BP4 BA1 PS1 PS3 PP3

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>A (p.Gly98Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code BS3 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: BS3: Level 1 assays (PMID 28645073 - Jiang et al., 2017) performed using heterologous cells (CHO-ldlA7) with Western blot, flow cytometry and confocal microscopy, showed normal expression (95%), binding (98%) and uptake (110%), consistent with no damaging effect.
Met criteria codes
BS3
Level 1 assays: PMID 28645073: - Heterologous cells (CHO-ldlA7) - WB, FACS and CLSM assays - Normal expression (95%), binding (98%) and uptake (110%) Functional study is consistent with no damaging effect.
Not Met criteria codes
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>C (p.Gly98Arg) (ClinVar ID 251119) - 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
PM2
PopMax MAF = 0.0002506 (0.02506%) in East Asian exomes+genomes (gnomAD v2.1.1).
BS1
FAF = 0.0001062 (0.01062%) in East Asian exomes (gnomAD v2.1.1).
BP4
REVEL = 0.696. It is not below 0.50
BA1
FAF = 0.0001062 (0.01062%) in East Asian exomes (gnomAD v2.1.1).
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>C (p.Gly98Arg) (ClinVar ID 251119) - 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
PS3
Level 1 assays: PMID 28645073: - Heterologous cells (CHO-ldlA7) - WB, FACS and CLSM assays - Normal expression (95%), binding (98%) and uptake (110%) Functional study is consistent with no damaging effect.
PP3
REVEL = 0.696. It is not above 0.75, splicing evaluation needed. Functional data on splicing not available. A) Variant not on limits. B) Variant does not create GT. C) No nearby GT Variant is predicted to alter splicing.
Curation History
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