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]
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Variant: NM_000527.5(LDLR):c.1301C>T (p.Thr434Met)

CA033501

251775 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: f83169fc-bfe0-4060-a806-1741515b098c

HGVS expressions

NM_000527.5:c.1301C>T
NM_000527.5(LDLR):c.1301C>T (p.Thr434Met)
NC_000019.10:g.11113392C>T
CM000681.2:g.11113392C>T
NC_000019.9:g.11224068C>T
CM000681.1:g.11224068C>T
NC_000019.8:g.11085068C>T
NG_009060.1:g.29012C>T
ENST00000558518.6:c.1301C>T
ENST00000252444.9:n.1555C>T
ENST00000455727.6:c.797C>T
ENST00000535915.5:c.1178C>T
ENST00000545707.5:c.920C>T
ENST00000557933.5:c.1301C>T
ENST00000558013.5:c.1301C>T
ENST00000558518.5:c.1301C>T
ENST00000559340.1:n.22C>T
ENST00000560173.1:n.300C>T
ENST00000560467.1:n.781C>T
NM_000527.4:c.1301C>T
NM_001195798.1:c.1301C>T
NM_001195799.1:c.1178C>T
NM_001195800.1:c.797C>T
NM_001195803.1:c.920C>T
NM_001195798.2:c.1301C>T
NM_001195799.2:c.1178C>T
NM_001195800.2:c.797C>T
NM_001195803.2:c.920C>T

Uncertain Significance

Met criteria codes 5
PP4 PM2 PM5 BP2 BP4
Not Met criteria codes 17
PS2 PS4 PS3 PS1 PP1 PP3 PM6 PM3 PM1 PM4 PVS1 BA1 BS2 BS4 BS3 BS1 BP3

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
The NM_000527.5(LDLR):c.1301C>T (p.Thr434Met) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PM5, PP4, BP2, and BP4 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 = 0.00007 (0.007%) in South Asian exomes+genomes (gnomAD v2.1.1). So PM2 is met. PM5: 3 other missense variants in the same codon: - NM_000527.5(LDLR):c.1301C>G (p.Thr434Arg) (ClinVar ID 251774) - Pathogenic by these guidelines - NM_000527.5(LDLR):c.1300A>C (p.Thr434Pro)(ClinVar ID 496018) - Unknown significance by these guidelines - NM_000527.5(LDLR):c.1301C>A (p.Thr434Lys) (ClinVar ID 251773) - Likely pathogenic by these guidelines There is 1 variant in the same codon classified as Pathogenic by these guidelines. PP4: Variant meets PM2 and is identified in 1 case with DLCN criteria>=6 from Robarts Research Institue. So PP4 is met. BP2: 1 case with DLCN≥6 and LDL-C 7.44 mmol/l and NM_000384.3(APOB):c.10580G>A (p.Arg3527Gln) variant from Robarts Research Institue (The APOB variant, although not classified with FH VCEP approved guidelines, is considered Pathogenic by the FH VCEP). BP4: REVEL = 0.47. It is below 0.5. Splicing evaluation required. 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 doesn't create AG or GT. Variant is not predicted to alter splicing. So BP4 is met.
Met criteria codes
PP4
Variant meets PM2 and is identified in 1 case with DLCN criteria>=6 from Robarts Research Institue.So PP4 is met
PM2
PopMax MAF = 0.00007 (0.007%) in South Asian exomes+genomes (gnomAD v2.1.1). So PM2 is met.
PM5
3 other missense variants in the same codon: - NM_000527.5(LDLR):c.1301C>G (p.Thr434Arg) (ClinVar ID 251774) - Pathogenic by these guidelines - NM_000527.5(LDLR):c.1300A>C (p.Thr434Pro)(ClinVar ID 496018) - Unknown significance by these guidelines - NM_000527.5(LDLR):c.1301C>A (p.Thr434Lys) (ClinVar ID 251773) - Likely pathogenic by these guidelines There is 1 variant in the same codon classified as Pathogenic by these guidelines.
BP2
1 case with DLCN≥6 and LDL-C 7.44 mmol/l and NM_000384.3(APOB):c.10580G>A (p.Arg3527Gln) variant from Robarts Research Institue (The APOB variant, although not classified with FH VCEP approved guidelines, is considered Pathogenic by the FH VCEP).
BP4
REVEL = 0.47. It is below 0.5. Splicing evaluation required. 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 doesn't create AG or GT. Variant is not predicted to alter splicing. So BP4 is met.
Not Met criteria codes
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 DLCN criteria>=6 from Robarts Research Institue.
PS3
No data available
PS1
No other missense variant in the same codon with the same amino acid change.
PP1
No data available.
PP3
REVEL = 0.47. It is not above 0.75, so splicing evaluation required. 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 doesn't create AG or GT. C) there is an AG nearby. Variant cryptic score= -9.13, Wild type cryptic score= -10.76; Var criptic/Wt criptic= 0.84, it is below 1.1. Var criptic/Wt score= -1.38. It is below 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
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.
BA1
PopMax FAF= 0.00001082.
BS2
No data available.
BS4
No data available.
BS3
No data available
BS1
PopMax FAF= 0.00001082.
BP3
No in-frame deletions/insertions
Approved on: 2022-10-28
Published on: 2022-12-24
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