rs769256610
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000388.4(CASR):c.427G>A(p.Gly143Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging 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. G143E) has been classified as Pathogenic.
Frequency
Consequence
NM_000388.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CASR | NM_000388.4 | c.427G>A | p.Gly143Arg | missense_variant | 3/7 | ENST00000639785.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CASR | ENST00000639785.2 | c.427G>A | p.Gly143Arg | missense_variant | 3/7 | 1 | NM_000388.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152168Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251306Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135818
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461814Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727224
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152168Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74336
ClinVar
Submissions by phenotype
Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 01, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 143 of the CASR protein (p.Gly143Arg). This variant is present in population databases (rs769256610, gnomAD 0.0009%). This missense change has been observed in individuals with familial hypocalciuric hypercalcemia (PMID: 19179454, 32347971, 32430905; Invitae). ClinVar contains an entry for this variant (Variation ID: 237770). 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. This variant disrupts the p.Gly143 amino acid residue in CASR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7726161, 8702647, 19389809, 23077345). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Nov 05, 2021 | The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic. Computational tools yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. Computational tools predict that this variant is damaging. - |
Familial hypocalciuric hypercalcemia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 07, 2023 | Variant summary: CASR c.427G>A (p.Gly143Arg) results in a non-conservative amino acid change located in the Receptor, ligand binding region domain (IPR001828) inside the Venus Flytrap module (VFT) (Wen_2021) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251306 control chromosomes. c.427G>A has been reported in the literature in individuals affected with Familial Hypocalciuric Hypercalcemia (example, Cole_2009, Mouly_2020, Mariathasan_2020). 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. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories 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