Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000527.5(LDLR):c.1495T>C (p.Ser499Pro)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA10585480

251870 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 03bd189a-bd23-41fd-808e-20e389a75be8

Approved on: 2024-02-23

Published on: 2024-10-07

HGVS expressions

NM_000527.5:c.1495T>C

NM_000527.5(LDLR):c.1495T>C (p.Ser499Pro)

NC_000019.10:g.11113671T>C

CM000681.2:g.11113671T>C

NC_000019.9:g.11224347T>C

CM000681.1:g.11224347T>C

NC_000019.8:g.11085347T>C

NG_009060.1:g.29291T>C

ENST00000252444.10:c.1753T>C

ENST00000559340.2:c.1495T>C

ENST00000560467.2:c.1375T>C

ENST00000558518.6:c.1495T>C

ENST00000252444.9:c.1749T>C

ENST00000455727.6:c.991T>C

ENST00000535915.5:c.1372T>C

ENST00000545707.5:c.1114T>C

ENST00000557933.5:c.1495T>C

ENST00000558013.5:c.1495T>C

ENST00000558518.5:c.1495T>C

ENST00000559340.1:c.216T>C

NM_000527.4:c.1495T>C

NM_001195798.1:c.1495T>C

NM_001195799.1:c.1372T>C

NM_001195800.1:c.991T>C

NM_001195803.1:c.1114T>C

NM_001195798.2:c.1495T>C

NM_001195799.2:c.1372T>C

NM_001195800.2:c.991T>C

NM_001195803.2:c.1114T>C

Likely Pathogenic

PM2 PS4_Moderate PP3 PP4 PP1_Moderate

PM3 PM5 PM1 PM6 BA1 BS2 BS4 BS3 BS1 BP2 BP4 BP1 BP5 PS2 PS1 PS3 PP2

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

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.1495T>C (p.Ser499Pro) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PS4_Moderate, PP1_Moderate, PP3 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 v4.0.0). PP3: REVEL = 0.758. PS4_Moderate, PP4: Variant meets PM2 and is identified in at least 6 unrelated index cases who fulfill criteria for FH (4 cases with DLCN score >=6 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France; 2 cases with possible FH by Simon Broome criteria from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, France). PP1_Moderate - Variant segregates with FH phenotype in 4 informative meiosis in 4 families from different labs (Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France; Service de Biochimie de Biologie Moléculaire, Hospices Civils de Lyon, France): 4 affected family members have the variant.

PM2

PM2_Met: This variant is absent from gnomAD (v4.0.0).

PS4_Moderate

PS4_Moderate: Variant meets PM2 and is identified in 6 unrelated cases (4 with DLCN score>=6 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière) and 2 with Simon Broome possible from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France).

PP3

PP3_Met: REVEL = 0.758.

PP4

PP4_Met: Variant meets PM2 and is identified in 6 probands (4 with DLCN score >=6 and 2 with Simon Broome possible).

PP1_Moderate

PP1_Moderate: Variant segregates with phenotype in 4 informative meioses in 4 families (2 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière) and 2 from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France).

PM3

Variant meets PM2 but is not identified in an index case with heterozygous or homozygous FH phenotype as well as LDLR variant, in trans, or APOB/PCSK9 variant classified as Pathogenic by these or general ACMG guidelines.

PM5

PM5_Not Met: There is 1 variant in the same codon (c.1496C>G (p.Ser499Cys)) but is not classified as pathogenic by these guidelines.

PM1

PM1_Not Met: Variant meets PM2 but is in exon 10.

PM6

No de novo cases were identified.

BA1

This variant is absent from gnomAD (v4.0.0).

BS2

Variant not identified in normolipidemic individuals

BS4

No instance of variant non-segregation with FH phenotype in at least 2 informative meioses from at least 2 families with at least one unaffected relative (LDL-C <50th centile) who is positive for the variant.

BS3

BS3_Not Met: Functional studies are not available.

BS1

This variant is absent from gnomAD (v4.0.0).

BP2

BP4

REVEL = 0.758. Score is not below 0.50.

BP1

Not applicable

BP5

not applicable

PS2

No de novo cases were identified.

PS1

Not applicable

PS3

PS3_Not Met: Functional studies are not available.

PP2

Not applicable

Curation History

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