Variant: NM_000527.5(LDLR):c.1567G>C (p.Val523Leu)

CA034835

993226 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: 9c75220d-903b-4d84-bf53-3b230c5618f3

Approved on: 2024-01-27

Published on: 2024-10-07

HGVS expressions

NM_000527.5:c.1567G>C
NM_000527.5(LDLR):c.1567G>C (p.Val523Leu)
NC_000019.10:g.11113743G>C
CM000681.2:g.11113743G>C
NC_000019.9:g.11224419G>C
CM000681.1:g.11224419G>C
NC_000019.8:g.11085419G>C
NG_009060.1:g.29363G>C
ENST00000252444.10:c.1825G>C
ENST00000559340.2:c.1567G>C
ENST00000560467.2:c.1447G>C
ENST00000558518.6:c.1567G>C
ENST00000252444.9:c.1821G>C
ENST00000455727.6:c.1063G>C
ENST00000535915.5:c.1444G>C
ENST00000545707.5:c.1186G>C
ENST00000557933.5:c.1567G>C
ENST00000558013.5:c.1567G>C
ENST00000558518.5:c.1567G>C
ENST00000559340.1:c.288G>C
NM_000527.4:c.1567G>C
NM_001195798.1:c.1567G>C
NM_001195799.1:c.1444G>C
NM_001195800.1:c.1063G>C
NM_001195803.1:c.1186G>C
NM_001195798.2:c.1567G>C
NM_001195799.2:c.1444G>C
NM_001195800.2:c.1063G>C
NM_001195803.2:c.1186G>C

Likely Pathogenic

• Met criteria codes: PM5 PM2 PP4 PP3

• Not Met criteria codes: BA1 PM3 PM1 PM6 BS2 BS4 BS3 BS1 PS2 PS4 PS3 PS1 BP2 BP4 BP1 BP5 PP1 PP2

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

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR): c.1567G>C (p.Val523Leu) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM5, PP3 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 = 0.00003 in South Asian exomes (gnomAD v2.1.1). PP3: REVEL = 0.904. PM5: There is 1 missense variant in the same codon, NM_000527.5(LDLR):c.1567G>A (p.Val523Met), classified as Pathogenic by these guidelines. PP4: Variant meets PM2 and is identified in 1 patient with possible FH by Simon Broome criteria from PMID 26748104 (Reiman et al., 2016).

Met criteria codes

• PM5: PM5 - There is 1 missense variant in the same codon (c.1567G>A (p.Val523Met)) classified as pathogenic by these guidelines.
• PM2: PM2 - PopMax MAF = 0.00003 in South Asian exomes (gnomAD v2.1.1).
• PP4: PP4 - Variant meets PM2 and is identified in 1 patient (PMID: 26748104) with Simon Broome score possible (family history of myocardial infarction and cholesterol levels greater than 7.5 mmol/l).
• PP3: PP3 - REVEL = 0.904. It is above 0.75, so PP3 is met.

Not Met criteria codes

• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM3: Variant meets PM2 but is not identified in an index case with heterozygous or homozygous FH phenotype as well as LDLR variant, in trans, or APOB/PCSK9 variant classified as Pathogenic by these or general ACMG guidelines.
• PM1: PM1 - Variant meets PM2 but it is in exon 10.
• PM6: No de novo cases were identified.
• BS2: Variant not identified in normolipidemic individuals
• BS4: No segregation data available
• BS3: No functional assays performed/found
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS2: No de novo cases were identified.
• PS4: PS4 - Variant meets PM2. It is identified in only 1 patient (PMID: 26748104) with Simon Broome score possible.
• PS3: No functional assays performed/found
• PS1: PS1 - There is one missense variant that leads to the same amino acid change (c.1567G>T (p.Val523Leu)) but it is not classified as pathogenic by these guidelines.
• BP2: Variant meets PM2 but is not identified in an index case with heterozygous or homozygous FH phenotype as well as LDLR variant, in trans, or APOB/PCSK9 variant classified as Pathogenic by these or general ACMG guidelines.
• BP4: REVEL = 0.904. Score is not below 0.50.
• BP1: Not applicable
• BP5: not applicable
• PP1: PP1 - No segregation data available
• PP2: Not applicable