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.1279A>C (p.Arg427=)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA033384

251764 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: e1a0ec5e-a3f6-416d-b5d0-f502d242d549

Approved on: 2023-01-27

Published on: 2024-12-15

HGVS expressions

NM_000527.5:c.1279A>C

NM_000527.5(LDLR):c.1279A>C (p.Arg427=)

NC_000019.10:g.11113370A>C

CM000681.2:g.11113370A>C

NC_000019.9:g.11224046A>C

CM000681.1:g.11224046A>C

NC_000019.8:g.11085046A>C

NG_009060.1:g.28990A>C

ENST00000252444.10:c.1537A>C

ENST00000559340.2:c.1279A>C

ENST00000560467.2:c.1159A>C

ENST00000558518.6:c.1279A>C

ENST00000252444.9:c.1533A>C

ENST00000455727.6:c.775A>C

ENST00000535915.5:c.1156A>C

ENST00000545707.5:c.898A>C

ENST00000557933.5:c.1279A>C

ENST00000558013.5:c.1279A>C

ENST00000558518.5:c.1279A>C

ENST00000560173.1:n.278A>C

ENST00000560467.1:c.759A>C

NM_000527.4:c.1279A>C

NM_001195798.1:c.1279A>C

NM_001195799.1:c.1156A>C

NM_001195800.1:c.775A>C

NM_001195803.1:c.898A>C

NM_001195798.2:c.1279A>C

NM_001195799.2:c.1156A>C

NM_001195800.2:c.775A>C

NM_001195803.2:c.898A>C

Likely Benign

PP4 PM2 BP4 BP2 BP7

PS1 PS2 PS3 PS4 PP3 PP2 PP1 PM6 PM1 PM3 PM4 PM5 PVS1 BA1 BS2 BS4 BS3 BS1 BP1 BP3

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

The NM_000527.5(LDLR):c.1279A>C (p.Arg427=) variant is classified as Likely Benign for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes BP2, BP4, BP7, PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 27 January 2023. The supporting evidence is as follows: PM2: PopMax MAF = 0.00006976 (0.006976%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1). BP4: No REVEL, splicing evaluation required. Functional data on splicing not available. A) variant not on limits B) does not create AG/GT C) variant is exonic and there is no AG/GT nearby Variant is not predicted to alter splicing. --- BP4 is met. BP7: Variant is synonymous and meets BP4. BP2: Variant identified in an index case with heterozygous FH phenotype (LDL-C=170mg/dL on statins) and LDLR c.530C>T (p.Ser177Leu) (confirmed in trans), classified as Pathogenic by these guidelines, from Cardiovascular Research Group, Instituto Nacional de Saúde Dr. Ricardo Jorge, Portugal. PP4: Variant meets PM2 and is identified in 1 index case with possible FH by Simon Broome criteria from Cardiovascular Research Group, Instituto Nacional de Saúde Dr. Ricardo Jorge, Portugal. Variant has 3 Supporting evidence codes towards Benign, enough to classify as Likely Benign and only 1 Moderate plus 1 Supporting evidence codes towards Pathogenic, so we are confident in classifying this variant as Likely Benign.

PP4

Variant meets PM2 and is identified in 1 index cases who fulfills SB possible FH from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, so PP4 is met.

PM2

PopMax MAF = 0.00006976 (0.006976%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1), so PM2 is met.

BP4

No REVEL, splicing evaluation required. Functional data on splicing not available. A) variant not on limits B) does not create AG/GT C) variant is exonic and there is no AG/GT nearby Variant is not predicted to alter splicing. --- BP4 is Met.

BP2

Variant identified in an index case with heterozygous FH phenotype (LDL-C=170mg/dl under statins) and LDLR: c.530C>T (p.Ser177Leu), confirmed in trans, classified as Pathogenic by these guidelines, from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, so BP2 is met.

BP7

Variant is synonymous and meets BP4.

PS1

Variant is synonymous, so PS1 is Not Met.

PS2

de novo occurrence data not reported, so PS2 is Not Met.

PS3

There are no functional studies reported for this variant, so PS3 is not met.

PS4

Variant meets PM2 and is identified in only 1 index cases who fulfills SB possible FH from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, so PS4 is not met.

PP3

PP2

Not applicable

PP1

Segregation data not reported, so PP1 is Not Met.

PM6

de novo occurrence data not reported, so PM6 is Not Met.

PM1

Variant meets PM2 but is not a missense variant in exon 4 and is not one of the highly conserved cysteine residues.

PM3

PM4

Variant does not meet PM2 and is synonymous, so PM4 is Not Met.

PM5

Variant is synonymous, so PM5 is Not Met.

PVS1

Variant is synonymous, so PVS1 is Not Met.

BA1

FAF = 0.00003422 (0.003422%) in European (non-Finnish) exomes (gnomAD v2.1.1), so BA1 is not met.

BS2

Variant identified in only 1 heterozygous non-affected (LDL<50th percentile) family member from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge, so BS2 is not met.

BS4

Variant does not segregate with FH phenotype in only 1 informative meiosis from 1 family from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, so BS4 is not met.

BS3

There are no functional studies reported for this variant, so BS3 is not met.

BS1

FAF = 0.00003422 (0.003422%) in European (non-Finnish) exomes (gnomAD v2.1.1), so BS1 is not met.

BP1

Not applicable

BP3

Not applicable

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.