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.44T>C (p.Leu15Pro)

CA10584732

250981 (ClinVar)

Gene: LDLR (HGNC:3949)

Condition: hypercholesterolemia, familial (MONDO:0007750)

Inheritance Mode: Semidominant inheritance

UUID: 5a4acf2a-a4d4-4d21-b7ac-83ea18a248e0

Approved on: 2022-08-28

Published on: 2022-08-28

HGVS expressions

NM_000527.5:c.44T>C

NM_000527.5(LDLR):c.44T>C (p.Leu15Pro)

NC_000019.10:g.11089592T>C

CM000681.2:g.11089592T>C

NC_000019.9:g.11200268T>C

CM000681.1:g.11200268T>C

NC_000019.8:g.11061268T>C

NG_009060.1:g.5212T>C

ENST00000558518.6:c.44T>C

ENST00000455727.6:c.44T>C

ENST00000535915.5:c.44T>C

ENST00000545707.5:c.44T>C

ENST00000557933.5:c.44T>C

ENST00000557958.1:n.130T>C

ENST00000558013.5:c.44T>C

ENST00000558518.5:c.44T>C

ENST00000560502.5:n.130T>C

NM_000527.4:c.44T>C

NM_001195798.1:c.44T>C

NM_001195799.1:c.44T>C

NM_001195800.1:c.44T>C

NM_001195803.1:c.44T>C

NM_001195798.2:c.44T>C

NM_001195799.2:c.44T>C

NM_001195800.2:c.44T>C

NM_001195803.2:c.44T>C

NR_163945.1:n.68A>G

Likely Pathogenic

PS4_Supporting PS3_Moderate PP4 PM2

BA1 BP5 BP7 BP2 BP3 BP4 BP1 BS4 BS3 BS1 BS2 PVS1 PP1 PP3 PP2 PS2 PS1 PM3 PM1 PM4 PM5 PM6

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 1.1

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.44T>C (p.Leu15Pro) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PS3_Moderate, PP4, and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met. PS3_moderate - Level 2 Assay: PMID:27175606: Heterologous cells (CHO), CLSM assays: LDLR retained in ER, no LDL-LDLR binding. LDL binding <70% wild type activity, so PS3_Moderate is met. PS4_supporting - Variant meets PM2 and is identified in - 2 unrelated index cases who fulfill Simon-Broome possible criteria for FH from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), - 1 case from PMID: 12052488 with LDL-C above 10 mmol/L (DLCN>6), from Sweden. 3 cases, so PS4_Supporting is met. PP4 - Variant meets PM2 and is identified in 3 unrelated index cases who fulfill FH clinical criteria (see PS4 for details).

PS4_Supporting

Variant meets PM2 and is identified in - 2 unrelated index cases who fulfill Simon-Broome possible criteria for FH from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), - 1 case from PMID: 12052488 with LDL-C above 10 mmol/L (DLCN>6), from Sweden. 3 cases, so PS4_Supporting is met

PS3_Moderate

Level 2 Assay: PMID:27175606 Heterologous cells (CHO), CLSM assays: LDLR retained in ER, no LDL-LDLR binding LDL binding <70% wild type activity, so PS3_Moderate is met

PP4

PM2

This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met.

BA1

This variant is absent from gnomAD (gnomAD v2.1.1)

BP5

not applicable

BP7

variant is missense, so not applicable

BP2

no index cases with other variants were identified

BP3

not applicable

BP4

REVEL = 0.675. It is not below 0.50, so BP4 is not met

BP1

not applicable

BS4

there is no segregation data

BS3

Level 2 Assay: PMID:27175606 Heterologous cells (CHO), CLSM assays: LDLR retained in ER, no LDL-LDLR binding LDL binding <70% wild type activity, so BS3 is not met

BS1

This variant is absent from gnomAD (gnomAD v2.1.1)

BS2

there is no data on normolipidemic individuals, so not met

PVS1

variant is missense and not in initiation codon, so not met

PP1

there is no segregation data

PP3

REVEL = 0.675. It is not above 0.75, so PP3 is not met

PP2

not applicable

PS2

no de novo occurrence was identified

PS1

There is no other missense variant that leads to the same amino acid change, so not met

PM3

no index cases with other variants were identified

PM1

variant is missense and meets PM2, but it is in exon 1 and does not alter Cys, so not met

PM4

variant is missense, so not applicable

PM5

there is 1 more missense variant in the same codon: NM_000527.5(LDLR):c.44T>A (p.Leu15His) (ClinVar ID 250980) - classified as VUS by these guidelines, so PM5 is not met

PM6

no de novo occurrence was identified

Curation History

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