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]

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Variant: NM_000527.5(LDLR):c.1954A>G (p.Met652Val)

CA023615

183129 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 712f30f7-22e8-4854-9aae-37a109496552

HGVS expressions

NM_000527.5:c.1954A>G

NM_000527.5(LDLR):c.1954A>G (p.Met652Val)

NC_000019.10:g.11120200A>G

CM000681.2:g.11120200A>G

NC_000019.9:g.11230876A>G

CM000681.1:g.11230876A>G

NC_000019.8:g.11091876A>G

NG_009060.1:g.35820A>G

ENST00000558518.6:c.1954A>G

ENST00000252444.9:n.2208A>G

ENST00000455727.6:c.1450A>G

ENST00000535915.5:c.1831A>G

ENST00000545707.5:c.1573A>G

ENST00000557933.5:c.1954A>G

ENST00000558013.5:c.1954A>G

ENST00000558518.5:c.1954A>G

ENST00000559340.1:n.535A>G

NM_000527.4:c.1954A>G

NM_001195798.1:c.1954A>G

NM_001195799.1:c.1831A>G

NM_001195800.1:c.1450A>G

NM_001195803.1:c.1573A>G

NM_001195798.2:c.1954A>G

NM_001195799.2:c.1831A>G

NM_001195800.2:c.1450A>G

NM_001195803.2:c.1573A>G

Uncertain Significance

PM2

PS1 PP3 PM1 PM5 BS3

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>G (p.Met652Val) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and BS3_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 follow: PM2_Met : Allele frequency is 0.00002 in European (Non-Finnish) subpopulation (>129178 alleles tested) in GnomAD (gnomAD v2.1.1).

PM2

Allele frequency is 0.00002 in European (Non-Finnish) subpopulation (>129178 alleles tested) in GnomAD (gnomAD v2.1.1).

PS1

no other variants at the same codon leading to the same aa change have been found in ClinVar

PP3

REVEL = 0.515, it is not above 0.75, splicing evaluation required. Functional data on splicing not available. A) variant not on limits B) creates a GT MES scores: variant de novo = -9.24, authentic wild-type = 10.28 Ratio: variant de novo/authentic wild-type score = -9.24/10.28 = -0.898 --- is not >0.9 C) no nearby GT --- PP3 is not met

PM1

Variant is in exon 13

PM5

2 variants were found in the same codon leading to different aa change. However 1 was classified as VUS and 1 as likely pathogenic by these guidelines.

BS3

the study PMID 25647241 does not look at the 3 steps of the LDLR cycle, expression, binding and uptake, it should not be considered towards BS3_Supporting

Approved on: 2022-12-23

Published on: 2022-12-23

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