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]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_000527.5(LDLR):c.148G>T (p.Ala50Ser)

CA023515

68099 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 7aea797c-2e2f-4ae1-a65b-1e4ca2e3f8e4
Approved on: 2024-10-28
Published on: 2025-01-20

HGVS expressions

NM_000527.5:c.148G>T
NM_000527.5(LDLR):c.148G>T (p.Ala50Ser)
NC_000019.10:g.11100303G>T
CM000681.2:g.11100303G>T
NC_000019.9:g.11210979G>T
CM000681.1:g.11210979G>T
NC_000019.8:g.11071979G>T
NG_009060.1:g.15923G>T
ENST00000252444.10:c.406G>T
ENST00000559340.2:c.148G>T
ENST00000560467.2:c.148G>T
ENST00000558518.6:c.148G>T
ENST00000252444.9:c.402G>T
ENST00000455727.6:c.148G>T
ENST00000535915.5:c.148G>T
ENST00000545707.5:c.148G>T
ENST00000557933.5:c.148G>T
ENST00000557958.1:n.234G>T
ENST00000558013.5:c.148G>T
ENST00000558518.5:c.148G>T
ENST00000560502.5:n.234G>T
NM_000527.4:c.148G>T
NM_001195798.1:c.148G>T
NM_001195799.1:c.148G>T
NM_001195800.1:c.148G>T
NM_001195803.1:c.148G>T
NM_001195798.2:c.148G>T
NM_001195799.2:c.148G>T
NM_001195800.2:c.148G>T
NM_001195803.2:c.148G>T
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Uncertain Significance

Not Met criteria codes 21
PS2 PS4 PS3 PS1 PP4 PP1 PP3 BA1 PM3 PM1 PM4 PM5 PM6 PM2 BS4 BS3 BS1 BS2 BP2 BP3 BP4

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

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
The NM_000527.5(LDLR):c.148G>T (p.Ala50Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying no ACMG/AMP evidence codes as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on October 28th, 2024.
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 doesn't meet PM2
PS3
No data available
PS1
No other missense variant in the codon with the same amino acid change
PP4
Variant doesn't meet PM2.
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
REVEL= 0.545. It is not above 0.75. Splicing evaluation required. A) variant not on limits. B) variant is exonic and at least 50bp downstream from the canonical acceptor site, but it does not create GT. C) No GT nearby. Variant is not predicted to alter splicing.
BA1
FAF= 0.0006315 (0.063%) in European (non-Finnish) exomes+genomes (gnomAD v4.1.0).
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
PM5
1 other missense variants in the same codon: - NM_000527.5(LDLR):c.148G>A (p.Ala50Thr) (ClinVar ID 251037) - Unknown significance by these guidelines There is no variant in the same codon classified as Pathogenic by these guidelines.
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
PopMax MAF = 0.0007738 (0.077%) in European (non-Finnish) exomes+genomes (gnomAD v4.1.0).
BS4
Variant does not segregate with FH phenotype in 1 informative meiosis from 1 family from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies
BS3
No data available
BS1
FAF= 0.0006315 (0.063%) in European (non-Finnish) exomes+genomes (gnomAD v4.1.0).
BS2
No data available
BP2
Variant identified in an index case with heterozygous FH phenotype (maximum LDL-c= 308mg/dl) and APOB variant c.12460G>T (p.Glu4154Ter), classified as Likely Pathogenic from Genomics Medicine Unit, Navarrabiomed, but not for FH. Patient also has another LDLR variant, c.2282C>T (p.Thr761Met), classified as unknown significance by these guidelines.
BP3
No in-frame deletions/insertions
BP4
REVEL= 0.545. It is not below 0.5.
Curation History
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