chr3-122254262-C-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000388.4(CASR):c.73C>T(p.Arg25*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,613,862 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 Likely pathogenic (★★).
Frequency
Consequence
NM_000388.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152048Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251326Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135840
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461814Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727204
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152048Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74254
ClinVar
Submissions by phenotype
not provided Pathogenic:5
The R25X nonsense variant in the CASR gene has been reported previously in patients with primary hyperparathyroidism and familial hypocacliuric hypercalcemia (Frank-Raue et al, 2011; Ward et al., 2006). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In addition, the R25X variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry by the NHLBI Exome Sequencing Project. In summary, we interpret R25X as a pathogenic variant. -
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CASR: PVS1:Strong, PS4:Moderate, PM2:Supporting -
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Autosomal dominant hypocalcemia 1 Pathogenic:1
A heterozygous nonsense variant was identified, NM_000388.3(CASR):c.73C>T in exon 2 of 7 of the CASR gene. This nonsense variant is predicted to create a change of arginine to a stop at amino acid position 25 of the protein, NP_000379.2(CASR):p.(Arg25*) resulting in the loss of normal protein function through nonsense-mediated decay (NMD). The variant is present in the gnomAD population database at a frequency of 0.0018% (5 heterozygotes). It has been previously reported as pathogenic and in patients with mild hypercalcaemia and hyperparathyroidism (ClinVar, Ward, B. et al. (2006), Frank-Raue, K. et al. (2011)). It has also been shown to segregate with the disease in one family (Ward, B. et al. (2006)). Other variants predicted to cause NMD have been reported as pathogenic in individuals with hyperparathyroidism and hypercalcemia (ClinVar). Based on information available at the time of curation, this variant has been classified as PATHOGENIC. -
Nephrolithiasis/nephrocalcinosis Pathogenic:1
The p.R25* pathogenic mutation (also known as c.73C>T), located in coding exon 1 of the CASR gene, results from a C to T substitution at nucleotide position 73. This changes the amino acid from an arginine to a stop codon within coding exon 1. This alteration has been identified in multiple families with familial hypocalciuric hypercalcemia (FHH) (Ward BK et al. Clin Endocrinol (Oxf), 2006 May;64:580-7; García-Castaño A et al. Eur J Endocrinol, 2019 Jan;180:59-70). Additionally, this alteration was identified in an individual diagnosed with hypercalcemia, hyperparathyroidism, kidney stones and hypertension (Frank-Raue K et al. Clin Endocrinol (Oxf), 2011 Jul;75:50-5). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Neonatal severe primary hyperparathyroidism Pathogenic:1
Variant summary: CASR c.73C>T (p.Arg25X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 8e-06 in 251326 control chromosomes. c.73C>T has been reported in the literature at a homozygous state in at-least one individual affected with Neonatal Severe Hyperparathyroidism and at a heterozygous state in one patient with familial hypocalciuric hypercalcaemia (example, Hannan_2012). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 22422767). ClinVar contains an entry for this variant (Variation ID: 372315). Based on the evidence outlined above, the variant was classified as pathogenic. -
Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia Pathogenic:1
This sequence change creates a premature translational stop signal (p.Arg25*) in the CASR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CASR are known to be pathogenic (PMID: 11807402, 14985373, 22422767). This variant is present in population databases (rs201633414, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with familial hypocalciuric hypercalcaemia (FHH) and primary hyperparathyroidism (HPT) (PMID: 16649980, 21521328). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this CASR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 606,512 individuals referred to our laboratory for CASR testing. ClinVar contains an entry for this variant (Variation ID: 372315). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Autosomal dominant hypocalcemia 1;C0342637:Familial hypocalciuric hypercalcemia 1;C1832615:Neonatal severe primary hyperparathyroidism;C2752062:Epilepsy, idiopathic generalized, susceptibility to, 8 Pathogenic:1
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CASR-related calcium metabolism disorders Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at