rs879254960
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate
The NM_000527.5(LDLR):āc.1612A>Gā(p.Thr538Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T538I) has been classified as Uncertain significance.
Frequency
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.1612A>G | p.Thr538Ala | missense_variant | 11/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.1612A>G | p.Thr538Ala | missense_variant | 11/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460670Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 726708
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Familial hypercholesterolemia Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 11, 2021 | This missense variant (also known as p.Thr517Ala in the mature protein) replaces threonine with alanine at codon 538 of the LDLR protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with familial hypercholesterolemia in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 05, 2023 | This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 538 of the LDLR protein (p.Thr538Ala). This variant has not been reported in the literature in individuals affected with LDLR-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt LDLR protein function. ClinVar contains an entry for this variant (Variation ID: 1171671). - |
Hypercholesterolemia, familial, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 23, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at