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.498C>T (p.Ala166=)

CA043710

328050 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: c11017c3-bd59-4caa-8e79-2ba6693d1fc0
Approved on: 2024-08-30
Published on: 2024-10-09

HGVS expressions

NM_000527.5:c.498C>T
NM_000527.5(LDLR):c.498C>T (p.Ala166=)
NC_000019.10:g.11105404C>T
CM000681.2:g.11105404C>T
NC_000019.9:g.11216080C>T
CM000681.1:g.11216080C>T
NC_000019.8:g.11077080C>T
NG_009060.1:g.21024C>T
ENST00000252444.10:c.756C>T
ENST00000559340.2:c.498C>T
ENST00000560467.2:c.498C>T
ENST00000558518.6:c.498C>T
ENST00000252444.9:c.752C>T
ENST00000455727.6:c.314-1988C>T
ENST00000535915.5:c.375C>T
ENST00000545707.5:c.314-1161C>T
ENST00000557933.5:c.498C>T
ENST00000558013.5:c.498C>T
ENST00000558518.5:c.498C>T
ENST00000560467.1:c.98C>T
NM_000527.4:c.498C>T
NM_001195798.1:c.498C>T
NM_001195799.1:c.375C>T
NM_001195800.1:c.314-1988C>T
NM_001195803.1:c.314-1161C>T
NM_001195798.2:c.498C>T
NM_001195799.2:c.375C>T
NM_001195800.2:c.314-1988C>T
NM_001195803.2:c.314-1161C>T
More

Likely Benign

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

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

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Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
The NM_000527.5(LDLR):c.498C>T (p.Ala166=) variant is classified as Likely Benign for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes BS1, BP4 and BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (spcification version 1.2) on 30 August 2024. The supporting evidence is as follows: BS1: FAF=0.004221 (0.42%) in African/African American exomes + genomes (gnomAD v4.1.0). BP4: No REVEL, splicing evaluation required. Functional data on splicing not available. A) not on limits. B) does not create a GT. C) there is a GT nearby. MES scores: variant cryptic = -2.92, wt cryptic = -2.92, canonical donor = 7.67. Cryptic scores are negative, so cryptic site is not used - variant is not predicted to alter splicing. BP7: Variant is synonymous and meets BP4.
Met criteria codes
BS1
FAF = 0.004221 (0.42%) in African/African American exomes + genomes (gnomAD v4.1.0). It is above 0.2%, so BS1 is met
BP7
Variant is synonymous and meets BP4.
BP4
No REVEL, splicing evaluation required. Functional data on splicing not available. A) not on limits. B) does not create a GT. C) there is a GT nearby. MES scores: variant cryptic = -2.92, wt cryptic = -2.92, canonical donor = 7.67. Cryptic scores are negative, so cryptic site is not used - Variant is not predicted to alter splicing.
Not Met criteria codes
PS2
no de novo occurrence
PS4
Variant was identified in 3 unrelated index cases from one lab, after alternative causes of high cholesterol were excluded (1 case with Simon Broome criteria of possible FH and 2 cases with DLCN criteria >=6 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, France). Variant does not meet PM2, so PS4 is not met.
PS3
no published functional studies
PS1
variant is synonymous, so not applicable
PP1
No family members tested
PP4
Variant was identified in 3 unrelated index cases from one lab, after alternative causes of high cholesterol were excluded (1 case with Simon Broome criteria of possible FH and 2 cases with DLCN criteria >=6 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, France). Variant does not meet PM2, so PP4 is not met.
PP3
No REVEL, splicing evaluation required. Functional data on splicing not available. A) not on limits. B) does not create a GT. C) there is a GT nearby. MES scores: variant cryptic = -2.92, wt cryptic = -2.92, canonical donor = 7.67. Cryptic scores are negative, so cryptic site is not used - Variant is not predicted to alter splicing.
PP2
not applicable
PVS1
variant is synonymous, so not applicable
PM3
Identified in 1 index case also heterozygous for LDLR variant c.1636G>A with LDL-c 250 mg/dl (not reported if LDL values are treated or untreated). Unknown if the 2 variants are in cis or trans, so PM3 is not met
PM1
variant is synonymous, so not applicable
PM4
variant is synonymous, so not applicable
PM5
variant is synonymous, so not applicable
PM6
no de novo occurrence
PM2
PopMax MAF = 0.004622 (0.4622%) in African/African American exomes + genomes (gnomAD v4.1.0). It is not below 0.02%, so not met
BA1
FAF = 0.004221 (0.42%) in African/African American exomes + genomes (gnomAD v4.1.0). It is not above 0.5%, so BA1 is not met
BS2
not identified in normolipidemic individuals
BS4
No family members tested
BS3
no published functional studies
BP5
not applicable
BP2
Identified in 1 index case also heterozygous for LDLR variant c.1636G>A with LDL-c 250 mg/dl (not reported if LDL values are treated or untreated). Unknown if the 2 variants are in cis or trans, so BP2 is not met
BP3
not applicable
BP1
not applicable
Curation History
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