NM_174936.4:c.706G>A
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PP3_ModerateBS2_Supporting
The NM_174936.4(PCSK9):c.706G>A(p.Gly236Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000384 in 1,613,126 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 Uncertain significance (★★).
Frequency
Consequence
NM_174936.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000328 AC: 5AN: 152242Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000602 AC: 15AN: 249196Hom.: 0 AF XY: 0.0000666 AC XY: 9AN XY: 135172
GnomAD4 exome AF: 0.0000390 AC: 57AN: 1460766Hom.: 0 Cov.: 81 AF XY: 0.0000578 AC XY: 42AN XY: 726700
GnomAD4 genome AF: 0.0000328 AC: 5AN: 152360Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 74498
ClinVar
Submissions by phenotype
Hypercholesterolemia, autosomal dominant, 3 Uncertain:2
This missense variant replaces glycine with serine at codon 236 of the PCSK9 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown this variant to cause a loss of PCSK9 function due to the failure of the mutant protein to exit the endoplasmic reticulum (PMID: 18266662). As a result, the cells expressing the mutant protein showed increased LDL uptake (PMID: 18266662). Consistent with this functional study, this variant has been reported in hypocholesterolemic individuals (PMID: 18266662, 34341098). To our knowledge, this variant has not been reported in individuals affected with PCSK9-related disorders in the literature. This variant has been identified in 16/280576 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although available evidence indicate this variant is unlikely to be disease-causing, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
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not specified Uncertain:1
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been in 1 individual with hypocholesterolemia - classified as DM in HGMD. An in vitro cleavage assay showed that the variant had a loss of function effect. Gain of function mutations in this gene lead to hypercholesterolemia, while loss of function lead to hypocholesterolemia. This variant is not classified in ClinVar. The variant was seen in 0.02% of South Asian chrs in gnomAD (6 chrs). -
Hypercholesterolemia, familial, 1 Uncertain:1
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not provided Uncertain:1
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Familial hypercholesterolemia Uncertain:1
This missense variant replaces glycine with serine at codon 236 of the PCSK9 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. A functional study has shown this variant to cause a loss of PCSK9 function due to the failure of the mutant protein to exit the endoplasmic reticulum (PMID: 18266662). As a result, the cells expressing the mutant protein showed increased LDL uptake (PMID: 18266662). Consistent with this functional study, this variant has been reported in two individuals with low circulating levels of LDL-C (PMID: 18266662, 34341098). To our knowledge, this variant has not been reported in individuals affected with PCSK9-related disorders in the literature. This variant has been identified in 16/280576 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although available evidence indicate this variant is unlikely to be disease-causing, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at