Evidence Repository
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.1868T>C (p.Ile623Thr)

CA037264

369855 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 0cf2579d-f345-4bf4-b577-f2f424de39fc
Approved on: 2023-04-28
Published on: 2023-04-30

HGVS expressions

NM_000527.5:c.1868T>C
NM_000527.5(LDLR):c.1868T>C (p.Ile623Thr)
NC_000019.10:g.11120114T>C
CM000681.2:g.11120114T>C
NC_000019.9:g.11230790T>C
CM000681.1:g.11230790T>C
NC_000019.8:g.11091790T>C
NG_009060.1:g.35734T>C
ENST00000558518.6:c.1868T>C
ENST00000252444.9:n.2122T>C
ENST00000455727.6:c.1364T>C
ENST00000535915.5:c.1745T>C
ENST00000545707.5:c.1487T>C
ENST00000557933.5:c.1868T>C
ENST00000558013.5:c.1868T>C
ENST00000558518.5:c.1868T>C
ENST00000559340.1:n.449T>C
NM_000527.4:c.1868T>C
NM_001195798.1:c.1868T>C
NM_001195799.1:c.1745T>C
NM_001195800.1:c.1364T>C
NM_001195803.1:c.1487T>C
NM_001195798.2:c.1868T>C
NM_001195799.2:c.1745T>C
NM_001195800.2:c.1364T>C
NM_001195803.2:c.1487T>C
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Uncertain Significance

Met criteria codes 3
BP2 PP4 PM2
Not Met criteria codes 18
BA1 BS4 BS3 BS1 BS2 PVS1 BP3 BP4 PS2 PS4 PS3 PS1 PP1 PP3 PM3 PM1 PM4 PM6

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.2

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
The NM_000527.5(LDLR):c.1868T>C (p.Ile623Thr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PP4, and BP2 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: PopMax MAF = 0.00005 (0.005%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1). So, PM2 is met. PP4: Variant meets PM2 and is identified in 1 case with Simon-Broome criteria of possible FH from Robarts Research Institute. So, PP4 is met. BP2: 1 individual from Robarts Research Institute with APOB c.10580G>A variant. Phenotype LDL 5.82 mmol/L - Heterozygous phenotype, c.10580G>A - Pathogenic using the general ACMG guidelines. So BP2 is met.
Met criteria codes
BP2
1 individual from Robarts Research Institute with APOB c.10580G>A variant. Phenotype LDL 5.82 mmol/L - Heterozygous phenotype, c.10580G>A - Pathogenic using the general ACMG guidelines. So BP2 is met.
PP4
Variant meets PM2 and is identified in 1 case with Simon-Broome criteria of possible FH from Robarts Research Institute. So, PP4 is met.
PM2
PopMax MAF = 0.00005 (0.005%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1). So, PM2 is met.
Not Met criteria codes
BA1
PopMax FAF= 0.00001121.
BS4
No data available
BS3
No data available.
BS1
PopMax FAF= 0.00001121.
BS2
No data available.
PVS1
Not a null variant
BP3
no in-frame deletions/insertions
BP4
REVEL=0.585. It is above 0.5.
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
Variant meets PM2 and is identified in 1 case with Simon-Broome criteria of possible FH from Robarts Research Institute
PS3
No data available.
PS1
No other missense variant with the same amino acid change.
PP1
No data available
PP3
REVEL=0.585. It is not above 0.75, so 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 = -3.31, wt cryptic = -2.30, canonical acceptor = 9.58. Ratio variant cryptic/wt cryptic: -3.31/-2.30 = 1.44 --- it is above 1.1 Ratio variant cryptic/canonical acceptor: -3.31/9.58 = -0.34--- it is below 0.9 Variant is not predicted to alter splicing.
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
Not in exon 4. Not a cysteine residue.
PM4
no in-frame deletions/insertions
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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