Submissions for variant NM_000388.4(CASR):c.73C>T (p.Arg25Ter)

gnomAD frequency: 0.00010  dbSNP: rs201633414

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413560	SCV000490452	pathogenic	not provided	2016-05-04	criteria provided, single submitter	clinical testing	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.
Invitae	RCV000457695	SCV000550973	pathogenic	Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1	2023-12-28	criteria provided, single submitter	clinical testing	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). 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.
Athena Diagnostics	RCV000413560	SCV000612679	likely pathogenic	not provided	2016-12-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004022152	SCV002673965	pathogenic	Nephrolithiasis/nephrocalcinosis	2021-08-11	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV003333060	SCV004041078	pathogenic	CASR-related calcium metabolism disorders	2023-08-30	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000413560	SCV005051184	likely pathogenic	not provided	2024-05-01	criteria provided, single submitter	clinical testing	CASR: PVS1:Strong, PS4:Moderate, PM2:Supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004586698	SCV005077214	pathogenic	Neonatal severe primary hyperparathyroidism	2024-04-18	criteria provided, single submitter	clinical testing	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.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000413560	SCV001930863	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000413560	SCV001957148	pathogenic	not provided		no assertion criteria provided	clinical testing