chr3-122261714-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000388.4(CASR):c.679C>T(p.Arg227Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000137 in 1,461,870 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R227R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000388.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CASR | NM_000388.4 | c.679C>T | p.Arg227Ter | stop_gained | 4/7 | ENST00000639785.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CASR | ENST00000639785.2 | c.679C>T | p.Arg227Ter | stop_gained | 4/7 | 1 | NM_000388.4 | P1 | |
CASR | ENST00000498619.4 | c.679C>T | p.Arg227Ter | stop_gained | 4/7 | 1 | |||
CASR | ENST00000638421.1 | c.679C>T | p.Arg227Ter | stop_gained | 4/7 | 5 | P1 | ||
CASR | ENST00000490131.7 | c.679C>T | p.Arg227Ter | stop_gained | 3/5 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461870Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2AN XY: 727236
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 06, 2018 | The R227X nonsense variant in the CASR gene has been reported previously in association with familial hypocalciuric hypercalcemia, as well as with neonatal severe primary hyperparathyroidism when observed in the homozygous state (Vargas-Poussou et al., 2016; Al-Khalaf et al., 2011). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant is not observed in large population cohorts (Lek et al., 2016). In summary, we consider this variant to be pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Dec 11, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Oct 09, 2018 | The variant creates a premature nonsense codon, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and not found in general population data. Damaging to protein function(s) relevant to disease mechanism. - |
Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 25, 2023 | This sequence change creates a premature translational stop signal (p.Arg227*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with neonatal severe primary hyperparathyroidism and familial hypocalciuric hypercalcemia (PMID: 20972686, 26963950, 27666534). ClinVar contains an entry for this variant (Variation ID: 532618). 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
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 11, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at