rs104893708
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP2PP3PP5
The NM_000388.4(CASR):c.374T>C(p.Leu125Pro) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L125F) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000388.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CASR | NM_000388.4 | c.374T>C | p.Leu125Pro | missense_variant | 3/7 | ENST00000639785.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CASR | ENST00000639785.2 | c.374T>C | p.Leu125Pro | missense_variant | 3/7 | 1 | NM_000388.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Autosomal dominant hypocalcemia 1 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | Feb 28, 2019 | This variant has been previously reported as a heterozygous change in patients with hypocalcemia (PMID: 11013439 12107202 12191970). Functional analysis revealed that the kinetics of activation of the p.Leu125Pro receptor expressed in HEK-293 cells, as assessed by measuring CaSR-stimulated changes in intracellular Ca(2+) and ERK activity, showed a dramatic reduction in the EC(50) for extracellular Ca(2+) compared with the wild-typ (PMID 12191970). The p.Leu125Pro variant is proposed to reduce NaCl reabsorption in the cortical thick ascending limb sufficiently to result in renal loss of NaCl with secondary hyperaldosteronism and hypokalemia (PMID 12191970). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.374T>C, p.Leu125Pro variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.374T>C, p.Leu125Pro variant is classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2002 | - - |
Autosomal dominant hypocalcemia 1;C0342637:Familial hypocalciuric hypercalcemia 1;C1832615:Neonatal severe primary hyperparathyroidism;C2752062:Epilepsy, idiopathic generalized, susceptibility to, 8 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 16, 2021 | - - |
Bartter syndrome with hypocalcemia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2002 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 11, 2021 | - - |
Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 06, 2023 | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 125 of the CASR protein (p.Leu125Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant hypocalcemia (PMID: 11701698, 12107202, 12191970). ClinVar contains an entry for this variant (Variation ID: 8346). 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. Experimental studies have shown that this missense change affects CASR function (PMID: 12191970, 25506941). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at