Variant: NM_000527.5(LDLR):c.1856T>G (p.Phe619Cys)

CA10585656

252085 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: 828e15e9-c755-4c90-bf79-2e2d5b7bca86

Approved on: 2022-02-10

Published on: 2022-04-25

HGVS expressions

NM_000527.5:c.1856T>G
NM_000527.5(LDLR):c.1856T>G (p.Phe619Cys)
NC_000019.10:g.11120102T>G
CM000681.2:g.11120102T>G
NC_000019.9:g.11230778T>G
CM000681.1:g.11230778T>G
NC_000019.8:g.11091778T>G
NG_009060.1:g.35722T>G
ENST00000558518.6:c.1856T>G
ENST00000252444.9:n.2110T>G
ENST00000455727.6:c.1352T>G
ENST00000535915.5:c.1733T>G
ENST00000545707.5:c.1475T>G
ENST00000557933.5:c.1856T>G
ENST00000558013.5:c.1856T>G
ENST00000558518.5:c.1856T>G
ENST00000559340.1:n.437T>G
NM_000527.4:c.1856T>G
NM_001195798.1:c.1856T>G
NM_001195799.1:c.1733T>G
NM_001195800.1:c.1352T>G
NM_001195803.1:c.1475T>G
NM_001195798.2:c.1856T>G
NM_001195799.2:c.1733T>G
NM_001195800.2:c.1352T>G
NM_001195803.2:c.1475T>G

Likely Pathogenic

• Met criteria codes: PM2 PS4_Supporting PP1 PP4 PP3

• Not Met criteria codes: PM5

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5 (LDLR): c.1856T>G (p.Phe619Cys) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PS4_Supporting, PP1) 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 Met: This variant is absent in gnomAD (gnomAD v2.1.1). PP3 Met: REVEL = 0.856, which is above the threshold of 0.75. PP4 Met: This variant meets PM2 and is identified >1 index cases who met clinical criteria for FH after alternative causes for high cholesterol were excluded. PS4_Supporting Met: Variant meets PM2, and is identified in 2 unrelated index cases who fulfil DLCN criteria for FH diagnosis from different labs. One index case is from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583897.1), another index case is reported from Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (PMID16250003, SCV000295717.2). PP1 Met: Variant segregates with FH phenotype in 2 informative meiosis in one family reported from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583897.1). There are two other variants in same codon: LDLR: NM_000527:c.1855T>C (p.Phe619Leu), LDLR: NM_000527:c.1856T>C (p.Phe619Ser), which are classified as Likely Pathogenic by these guidelines. Neither variant is classified as Pathogenic, therefore PM5 is not met.

Met criteria codes

• PM2: This variant is absent in gnomAD (gnomAD v2.1.1).
• PS4_Supporting: Variant meets PM2, and is identified in 2 unrelated index cases fulfil DLCN criteria for FH diagnosis from different labs. One index case is from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583897.1), another index case is reported from Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (PMID16250003, SCV000295717.2).
• PP1: Variant segregates with FH phenotype in 2 informative meiosis in one family reported from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583897.1).
• PP4: This variant meets PM2 and is identified >1 index cases who met clinical criteria for FH after alternative causes for high cholesterol were excluded.
• PP3: REVEL = 0.856, which is above the threshold of 0.75.

Not Met criteria codes

• PM5: There are two other variants in same codon: LDLR: NM_000527:c.1855T>C (p.Phe619Leu), LDLR: NM_000527:c.1856T>C (p.Phe619Ser), which are classified as Likely Pathogenic by these guidelines. Neither variant is classified as Pathogenic, therefore PM5 is not met.