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]

Link to SEPIO compliant JSON-LD document

Variant: NM_000527.5(LDLR):c.1954A>T (p.Met652Leu)

CA404093163

927435 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: ca6ebdf3-12e1-49a2-b65e-3eeb6809019e

HGVS expressions

NM_000527.5:c.1954A>T

NM_000527.5(LDLR):c.1954A>T (p.Met652Leu)

NC_000019.10:g.11120200A>T

CM000681.2:g.11120200A>T

NC_000019.9:g.11230876A>T

CM000681.1:g.11230876A>T

NC_000019.8:g.11091876A>T

NG_009060.1:g.35820A>T

ENST00000558518.6:c.1954A>T

ENST00000252444.9:n.2208A>T

ENST00000455727.6:c.1450A>T

ENST00000535915.5:c.1831A>T

ENST00000545707.5:c.1573A>T

ENST00000557933.5:c.1954A>T

ENST00000558013.5:c.1954A>T

ENST00000558518.5:c.1954A>T

ENST00000559340.1:n.535A>T

NM_000527.4:c.1954A>T

NM_001195798.1:c.1954A>T

NM_001195799.1:c.1831A>T

NM_001195800.1:c.1450A>T

NM_001195803.1:c.1573A>T

NM_001195798.2:c.1954A>T

NM_001195799.2:c.1831A>T

NM_001195800.2:c.1450A>T

NM_001195803.2:c.1573A>T

Uncertain Significance

PM2 BP4

PS3 PS1 PM1 PM5 PP1

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.1954A>T (p.Met652Leu) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and BP4 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 follow: PM2_Met : the variant was absent from controls in Gnomad database (gnomAD v2.1.1). BP4_Met : REVEL score is 0.252, splicing evaluation required. Functional data on splicing not available. A) Variant not on limits B) variant is exonic and at least 50bp upstream from canonical donor site, but does not create GT C) variant is exonic and there is no GT nearby Variant is not predicted to alter splicing.

PM2

the variant was absent from controls in Gnomad database (gnomAD v2.1.1).

BP4

REVEL score is 0.252, splicing evaluation required. Functional data on splicing not available. A) Variant not on limits B) variant is exonic and at least 50bp upstream from canonical donor site, but does not create GT C) variant is exonic and there is no GT nearby Variant is not predicted to alter splicing.

PS3

No functional data available

PS1

no variant at the same codon leading to the same aa change are reported

PM1

Variant is in exon 13

PM5

2 variants found in the same codon leading to different aa change are not classified as pathogenic by these guidelines

PP1

no segregation data available

Approved on: 2022-08-29

Published on: 2022-12-23

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