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.1749C>G (p.His583Gln)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA404089716

441220 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 8625c1db-5d72-4fd0-baab-8f9639bc9984

Approved on: 2023-11-07

Published on: 2024-12-24

HGVS expressions

NM_000527.5:c.1749C>G

NM_000527.5(LDLR):c.1749C>G (p.His583Gln)

NC_000019.10:g.11116902C>G

CM000681.2:g.11116902C>G

NC_000019.9:g.11227578C>G

CM000681.1:g.11227578C>G

NC_000019.8:g.11088578C>G

NG_009060.1:g.32522C>G

ENST00000252444.10:c.2007C>G

ENST00000559340.2:c.1705+690C>G

ENST00000560467.2:c.1629C>G

ENST00000558518.6:c.1749C>G

ENST00000252444.9:c.2003C>G

ENST00000455727.6:c.1245C>G

ENST00000535915.5:c.1626C>G

ENST00000545707.5:c.1368C>G

ENST00000557933.5:c.1749C>G

ENST00000558013.5:c.1749C>G

ENST00000558518.5:c.1749C>G

ENST00000559340.1:c.426+690C>G

NM_000527.4:c.1749C>G

NM_001195798.1:c.1749C>G

NM_001195799.1:c.1626C>G

NM_001195800.1:c.1245C>G

NM_001195803.1:c.1368C>G

NM_001195798.2:c.1749C>G

NM_001195799.2:c.1626C>G

NM_001195800.2:c.1245C>G

NM_001195803.2:c.1368C>G

Uncertain Significance

PM5 PM2 PP3

PVS1 BA1 PM3 PM4 PM1 PM6 BS4 BS3 BS1 BS2 BP7 BP5 BP2 BP3 BP4 BP1 PS2 PS4 PS1 PS3 PP4 PP1 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

NM_000527.5(LDLR):c.1749C>G (p.His583Gln) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM5 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 7 November 2023. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PP3: REVEL = 0.805. PM5: There is 1 variant in the same codon classified as Pathogenic by these guidelines, NM_000527.5(LDLR):c.1747C>T (p.His583Tyr) (ClinVar ID: 200921).

PM5

NM_000527.5(LDLR):c.1747C>T (p.His583Tyr) (ClinVar ID: 200921) considered as pathogenic by these guidelines.

PM2

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

PP3

REVEL = 0.805. It is above 0.75, so PP3 is met.

PVS1

Missense variant - LDLR gene, exon 12

BA1

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

PM3

Not identified in index cases with more than 1 variant

PM4

Missense variant - LDLR gene, exon 12

PM1

Variant in exon 12 of the LDLR gene (not located at exon 4)

PM6

No de novo occurrence

BS4

not met, (no information of index cases or report of segregation data/cases).

BS3

not met (no information or reports of functional data).

BS1

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

BS2

not met, (no information of index cases or report of segregation data/cases).

BP7

Missense variant - LDLR gene, exon 12

BP5

N/A according to FHVCEP guidelines

BP2

Not identified in index cases with more than 1 variant

BP3

Missense variant - LDLR gene, exon 12

BP4

REVEL = 0.805. It is not bellow 0.5, so BP4 is not met.

BP1

N/A according to FHVCEP guidelines

PS2

No de novo occurrence

PS4

not met, (no information of index cases or report of segregation data/cases).

PS1

Another variant gives the same amino acid change, NM_000527.5(LDLR):c.1749C>A (p.His583Gln) (ClinVar ID: 252014) but is only classified as likely pathogenic by these guidelines.

PS3

not met (no information or reports of functional data).

PP4

not met, (no information of index cases or report of segregation data/cases).

PP1

not met, (no information of index cases or report of segregation data/cases).

PP2

N/A according to FHVCEP guidelines

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.