rs875989919
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000527.5(LDLR):āc.1330T>Cā(p.Ser444Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S444F) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.1330T>C | p.Ser444Pro | missense_variant | 9/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.1330T>C | p.Ser444Pro | missense_variant | 9/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes Cov.: 29
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461688Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727140
GnomAD4 genome Cov.: 29
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital | Jun 09, 2008 | - - |
Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
Likely pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 08, 2017 | The S444P variant (reported as S423P due to historic nomenclature) has been reported previously in a few unrelated individuals with familial hypercholesterolemia, two of whom harbored a second LDLR variant (Laurie et al., 2004; Kusters et al., 2013). The S444P variant is not observed in large population cohorts (Lek et al., 2016). The S444P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs within the LDL-receptor class B 2 repeat region. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret S444P as a likely pathogenic variant. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at