Variant: NM_000527.5(LDLR):c.1875C>T (p.Asn625=)

CA023600

68102 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: 7031c563-9112-4d59-afbf-40f361d8e6f6

HGVS expressions

NM_000527.5:c.1875C>T
NM_000527.5(LDLR):c.1875C>T (p.Asn625=)
NC_000019.10:g.11120121C>T
CM000681.2:g.11120121C>T
NC_000019.9:g.11230797C>T
CM000681.1:g.11230797C>T
NC_000019.8:g.11091797C>T
NG_009060.1:g.35741C>T
ENST00000558518.6:c.1875C>T
ENST00000252444.9:n.2129C>T
ENST00000455727.6:c.1371C>T
ENST00000535915.5:c.1752C>T
ENST00000545707.5:c.1494C>T
ENST00000557933.5:c.1875C>T
ENST00000558013.5:c.1875C>T
ENST00000558518.5:c.1875C>T
ENST00000559340.1:n.456C>T
NM_000527.4:c.1875C>T
NM_001195798.1:c.1875C>T
NM_001195799.1:c.1752C>T
NM_001195800.1:c.1371C>T
NM_001195803.1:c.1494C>T
NM_001195798.2:c.1875C>T
NM_001195799.2:c.1752C>T
NM_001195800.2:c.1371C>T
NM_001195803.2:c.1494C>T

Likely Benign

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Conflicting Evidence"

• Met criteria codes: PP1 BP7 BP2 BP4

• Not Met criteria codes: PP4 PP3 PM6 PM2 PM3 PM1 PM4 PM5 PVS1 BA1 BS2 BS4 BS3 BS1 BP3 PS2 PS4 PS3 PS1

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.1875C>T (p.Asn625=) variant is classified as Likely Benign for Familial Hypercholesterolemia by applying evidence codes PP1, BP2, BP4, and BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). Variant has 3 supporting evidence codes towards Benign, enough to classify as Likely benign, and only 1 supporting evidence codes towards Pathogenic. The Benign criteria overwhelms the Pathogenic criteria, so we are confident in classifying this variant as Likely benign. The supporting evidence is as follows: PP1: Variant segregates with FH phenotype in 2 informative meioses in 1 families from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge. So PP1 is met. BP2: 1 individual from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge with LDLR c.1598G>A. Phenotype LDL 168mg/dl under statins - Htz phenotype, c.1598G>A - Pathogenic by these guidelines. BP4: No REVEL available, splicing evaluation needed. Functional data on splicing not available. A) variant not on limits. B) variant is exonic and at least 50bp upstream from the canonical donor site, but it does not create AG. C) there is an AG nearby. MES scores: variant cryptic = -1.41, wt cryptic = -2.30, canonical acceptor = 9.58. Ratio variant cryptic/wt cryptic: -1.41/-2.30 = 0.61 --- it is not above 1.1 Ratio variant cryptic/canonical acceptor: -1.41/9.58 = 0.15--- it is not above 0.9 Variant is not predicted to alter splicing. So BP4 is met. BP7: Variant is synonymous and meets BP4.

Met criteria codes

• PP1: Variant segregates with FH phenotype in 2 informative meioses in 1 families from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge. So PP1 is met.
• BP7: Variant is synonymous and meets BP4.
• BP2: 1 individual from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge with LDLR c.1598G>A. Phenotype LDL 168mg/dl under statins - Htz phenotype, c.1598G>A - Pathogenic by these guidelines.
• BP4: No REVEL available, splicing evaluation needed. Functional data on splicing not available. A) variant not on limits. B) variant is exonic and at least 50bp upstream from the canonical donor site, but it does not create AG. C) there is an AG nearby. MES scores: variant cryptic = -1.41, wt cryptic = -2.30, canonical acceptor = 9.58. Ratio variant cryptic/wt cryptic: -1.41/-2.30 = 0.61 --- it is not above 1.1 Ratio variant cryptic/canonical acceptor: -1.41/9.58 = 0.15--- it is not above 0.9 Variant is not predicted to alter splicing. So BP4 is met.

Not Met criteria codes

• PP4: Variant doesn't meet PM2.
• PP3: No REVEL available, splicing evaluation needed. Functional data on splicing not available. A) variant not on limits. B) variant is exonic and at least 50bp upstream from the canonical donor site, but it does not create AG. C) there is an AG nearby. MES scores: variant cryptic = -1.41, wt cryptic = -2.30, canonical acceptor = 9.58. Ratio variant cryptic/wt cryptic: -1.41/-2.30 = 0.61 --- it is not above 1.1 Ratio variant cryptic/canonical acceptor: -1.41/9.58 = 0.15--- it is not above 0.9 Variant is not predicted to alter splicing.
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM2: PopMax MAF = 0.00059 (0.059%) in Latino (gnomAD v2.1.1).
• PM3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: Not on exon 4. Not a cysteine residue.
• PM4: No in-frame deletions/insertions
• PM5: The current variant is in a non-coding region.
• PVS1: Not a null variant
• BA1: PopMax FAF = 0.0003355 ( 0.03355%)
• BS2: No data available
• BS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: PopMax FAF = 0.0003355 ( 0.03355%)
• BP3: No in-frame deletions/insertions
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: Variant doesn't meet PM2.
• PS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS1: The current variant is in a non-coding region.

Approved on: 2023-04-28

Published on: 2023-04-30