chr3-122284403-G-A
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PP2PP3_ModeratePP5_Very_Strong
The NM_000388.4(CASR):c.2449G>A(p.Val817Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V817L) has been classified as Uncertain significance.
Frequency
Consequence
NM_000388.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CASR | NM_000388.4 | c.2449G>A | p.Val817Ile | missense_variant | 7/7 | ENST00000639785.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CASR | ENST00000639785.2 | c.2449G>A | p.Val817Ile | missense_variant | 7/7 | 1 | NM_000388.4 | P1 | |
CASR | ENST00000498619.4 | c.2479G>A | p.Val827Ile | missense_variant | 7/7 | 1 | |||
CASR | ENST00000638421.1 | c.2449G>A | p.Val817Ile | missense_variant | 7/7 | 5 | P1 | ||
CASR | ENST00000490131.7 | c.2218G>A | p.Val740Ile | missense_variant | 5/5 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 71
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 04, 2019 | Not found in the total gnomAD dataset, and the data is high quality (0/283120 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Damaging to protein function(s) relevant to disease mechanism. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 16, 2021 | Published functional studies demonstrate V817I showed reduced cell surface expression compared to wild type, as well as reduced Ca2+ potency in intracellular Ca2+ mobilization and reduced ERK1/2 phosphorylation (Leach et al., 2012); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27746744, 19779033, 8675635, 17039419, 24111791, 22798347, 19389809, 8878438, 17284438, 11013439, 11762699, 12890593, 23372019) - |
Hypertrophic cardiomyopathy;C0020437:Hypercalcemia;C0020599:Hypocalciuria;C0262587:Parathyroid gland adenoma Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 05, 2015 | - - |
Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 19, 2021 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects CASR function (PMID: 8878438, 17284438, 22798347, 23372019). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 374153). This missense change has been observed in individuals with familial hypocalciuric hypercalcemia (FHH) (PMID: 8675635). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with isoleucine at codon 817 of the CASR protein (p.Val817Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. - |
Autosomal dominant hypocalcemia 1;C0342637:Familial hypocalciuric hypercalcemia 1;C1832615:Neonatal severe primary hyperparathyroidism;C2752062:Epilepsy, idiopathic generalized, susceptibility to, 8 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 05, 2022 | - - |
Familial hypocalciuric hypercalcemia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 25, 2023 | Variant summary: CASR c.2449G>A (p.Val817Ile) results in a conservative amino acid change located in the receptor calcium binding region (IPR001828) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251330 control chromosomes (gnomAD). c.2449G>A has been reported in the literature in individuals affected with Familial Hypocalciuric Hypercalcemia (examples: Pearce_ 1995 and Vargas-Poussou_ 2016). These data indicate that the variant is likely to be associated with disease. Multiple studies have shown this variant leads to reduced cell surface expression, reduced Ca2+ sensitivity and reduced ERK1/2 phosphorylation compared to wild type (examples: Pearce_1996, Hu_2005, Huang_2007, Leach_2013, White_2018). The following publications have been ascertained in the context of this evaluation (PMID: 8675635, 17284438, 8878438, 15591042, 19389809, 26963950, 23372019). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at