chr10-43111342-G-C
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3
The NM_020975.6(RET):āc.1399G>Cā(p.Val467Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,614,138 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 (ā ā ). Synonymous variant affecting the same amino acid position (i.e. V467V) has been classified as Likely benign.
Frequency
Consequence
NM_020975.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RET | NM_020975.6 | c.1399G>C | p.Val467Leu | missense_variant | 7/20 | ENST00000355710.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RET | ENST00000355710.8 | c.1399G>C | p.Val467Leu | missense_variant | 7/20 | 5 | NM_020975.6 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000328 AC: 5AN: 152250Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251450Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135912
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461770Hom.: 0 Cov.: 58 AF XY: 0.00000413 AC XY: 3AN XY: 727192
GnomAD4 genome AF: 0.0000328 AC: 5AN: 152368Hom.: 0 Cov.: 34 AF XY: 0.0000268 AC XY: 2AN XY: 74510
ClinVar
Submissions by phenotype
Multiple endocrine neoplasia, type 2 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | This missense variant replaces valine with leucine at codon 467 of the RET protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RET-related disorders in the literature. This variant has been identified in 5/251450 chromosomes 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 | Jan 18, 2024 | This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 467 of the RET protein (p.Val467Leu). This variant is present in population databases (rs200334340, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with RET-related conditions. ClinVar contains an entry for this variant (Variation ID: 432998). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Jul 13, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 02, 2022 | The p.V467L variant (also known as c.1399G>C), located in coding exon 7 of the RET gene, results from a G to C substitution at nucleotide position 1399. The valine at codon 467 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Multiple endocrine neoplasia type 2A;C0025269:Multiple endocrine neoplasia type 2B;C0031511:Pheochromocytoma;C1833921:Familial medullary thyroid carcinoma;C3888239:Hirschsprung disease, susceptibility to, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 11, 2022 | - - |
Multiple endocrine neoplasia type 2A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Sep 22, 2022 | The RET c.1399G>C (p.Val467Leu) missense change has a maximum subpopulation frequency of 0.0035% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in the literature in individuals with multiple endocrine neoplasia type 2. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. - |
Hirschsprung disease, susceptibility to, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 26, 2023 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 29, 2017 | The V467L variant in the RET gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The V467L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. We consider it to be a variant of uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at