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.2050G>A (p.Ala684Thr)

CA038311

252192 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
UUID: c82cc57e-8c67-461c-aa6b-22e0178cec0a
Approved on: 2025-02-20
Published on: 2025-06-17

HGVS expressions

NM_000527.5:c.2050G>A
NM_000527.5(LDLR):c.2050G>A (p.Ala684Thr)
NC_000019.10:g.11120432G>A
CM000681.2:g.11120432G>A
NC_000019.9:g.11231108G>A
CM000681.1:g.11231108G>A
NC_000019.8:g.11092108G>A
NG_009060.1:g.36052G>A
ENST00000252444.10:c.2308G>A
ENST00000559340.2:c.*119G>A
ENST00000560467.2:c.1930G>A
ENST00000558518.6:c.2050G>A
ENST00000252444.9:c.2304G>A
ENST00000455727.6:c.1546G>A
ENST00000535915.5:c.1927G>A
ENST00000545707.5:c.1606+199G>A
ENST00000557933.5:c.2050G>A
ENST00000558013.5:c.2050G>A
ENST00000558518.5:c.2050G>A
NM_000527.4:c.2050G>A
NM_001195798.1:c.2050G>A
NM_001195799.1:c.1927G>A
NM_001195800.1:c.1546G>A
NM_001195803.1:c.1606+199G>A
NM_001195798.2:c.2050G>A
NM_001195799.2:c.1927G>A
NM_001195800.2:c.1546G>A
NM_001195803.2:c.1606+199G>A
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Uncertain Significance

Met criteria codes 4
PM2 PP4 PP1 PP3
Not Met criteria codes 2
PM5 PS4

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.2050G>A (p.Ala684Thr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP1, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 20 February 2025. The supporting evidence is as follows: PM2: PopMax MAF = 0.01337% in East Asian exomes/genomes (gnomAD v4.1.0). PP3: REVEL score = 0.807. PP4: 1 case with DLCN>=6 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, France. PP1: Variant segregates with FH phenotype in 2 informative meioses from 1 family (Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, France): 1 affected family member has the variant and 1 non-affected family member does not have the variant.
Met criteria codes
PM2
PopMax MAF = 0.0001337 (0.01337%) in East Asian exomes/genomes (gnomAD v4.1.0).
PP4
One patient from the Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière) fulfils DLCN >=6
PP1
This variant has been reported to segregate with FH phenotype in 2 informative meioses from 1 family (Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière)). Proband Dutch lipid clinic network >=6; 1 family member positive for variant with LDL-C >75th percentile and 1 family member negative for variant with LDL-C <50th percentile.
PP3
REVEL score = 0.807.
Not Met criteria codes
PM5
No missense variants at the same codon predict a different amino acid change classified as pathogenic.
PS4
Besides the variant was identified in 1 FH case Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), the same variant was also identified in a patient reported PMID 11005141, however, the patient did not fulfill the criteria for a definite FH diagnosis.
Curation History
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