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.313+6T>C

CA10584845

251138 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: b5243326-9305-47e1-b66c-087409935645

HGVS expressions

NM_000527.5:c.313+6T>C

NM_000527.5(LDLR):c.313+6T>C

NC_000019.10:g.11102792T>C

CM000681.2:g.11102792T>C

NC_000019.9:g.11213468T>C

CM000681.1:g.11213468T>C

NC_000019.8:g.11074468T>C

NG_009060.1:g.18412T>C

ENST00000558518.6:c.313+6T>C

ENST00000252444.9:n.567+6T>C

ENST00000455727.6:c.313+6T>C

ENST00000535915.5:c.191-2428T>C

ENST00000545707.5:c.313+6T>C

ENST00000557933.5:c.313+6T>C

ENST00000557958.1:n.405T>C

ENST00000558013.5:c.313+6T>C

ENST00000558518.5:c.313+6T>C

NM_000527.4:c.313+6T>C

NM_001195798.1:c.313+6T>C

NM_001195799.1:c.191-2428T>C

NM_001195800.1:c.313+6T>C

NM_001195803.1:c.313+6T>C

NM_001195798.2:c.313+6T>C

NM_001195799.2:c.191-2428T>C

NM_001195800.2:c.313+6T>C

NM_001195803.2:c.313+6T>C

Uncertain Significance

PM2 PS3_Supporting PP4

PM3 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.313+6T>C variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4, PS3_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). PP4: Variant meets PM2 and is identified in 1 index case who fulfils Simon Brome criteria for possible FH after alternative causes of high cholesterol were excluded, reported by Bourbon et al from Unidade de Investigação Cardiovascular, Instituto Nacional de Saúde Dr. Ricardo Jorge, Lisboa, Portugal (PMID 19411563). PS3_Supporting: Level 3 experiment, heterozygous patients’ lymphocytes were used for RNA assay and exon 3 skipping (p.Leu64_Pro105delinsSer) was observed, reported by Bourbon et al (PMID 19411563). PM3 not met: This variant is identified in an index case with one other variant, LDLR c.1291G>A (p.Ala431Thr), classified as Pathogenic by these guidelines, in trans, reported by Bourbon et al (PMID 19411563).However, patient’s untreated LDL-C is 435mg/dl, which is under 500mg/dl, therefore PM3 is not met. PP1 not met: Variant segregates with FH phenotype in 1 (less than 2) informative meiosis from 1 family who was tested positive for the variant with LDL-C > 75th percentile, reported by Bourbon et al (PMID 19411563).

PM2

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

PS3_Supporting

Level 3 experiment, heterozygous patients’ lymphocytes were used for RNA assay and exon 3 skipping (p.Leu64_Pro105delinsSer) was observed, reported by Bourbon et al (PMID 19411563).

PP4

Variant meets PM2 and is identified in 1 index case who fulfils Simon Brome criteria for possible FH after alternative causes of high cholesterol were excluded, reported by Bourbon et al from Unidade de Investigação Cardiovascular, Instituto Nacional de Saúde Dr. Ricardo Jorge, Lisboa, Portugal (PMID 19411563).

PM3

This variant is identified in an index case with one other variant, LDLR c.1291G>A (p.Ala431Thr), classified as Pathogenic by these guidelines, in trans, reported by Bourbon et al (PMID 19411563).However, patient’s untreated LDL-C is 435mg/dl, which is under 500mg/dl, therefore PM3 is not met.

PP1

Variant segregates with FH phenotype in 1 (less than 2) informative meiosis from 1 family who was tested positive for the variant with LDL-C > 75th percentile, reported by Bourbon et al (PMID 19411563).

Approved on: 2022-08-26

Published on: 2022-12-23

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