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]

Link to SEPIO compliant JSON-LD document

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

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

Uncertain Significance

PM2 BP2 PP4

PM6 PM3 PM1 PM4 PVS1 BS4 BS3 BS1 BS2 BP3 BP4 BA1 PS2 PS4 PS3 PS1 PP1 PP3

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

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.

PM2

PopMax MAF = 0.00005 (0.005%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1). So, PM2 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.

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.

PM6

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

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

PVS1

Not a null variant

BS4

No data available

BS3

No data available.

BS1

PopMax FAF= 0.00001121.

BS2

No data available.

BP3

no in-frame deletions/insertions

BP4

REVEL=0.585. It is above 0.5.

BA1

PopMax FAF= 0.00001121.

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.

Approved on: 2023-04-28

Published on: 2023-04-30

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