rs267599574
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4_Moderate
The NM_000388.4(CASR):c.1327C>A(p.Leu443Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000149 in 1,613,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L443F) has been classified as Uncertain significance.
Frequency
Consequence
NM_000388.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CASR | NM_000388.4 | c.1327C>A | p.Leu443Ile | missense_variant | 4/7 | ENST00000639785.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CASR | ENST00000639785.2 | c.1327C>A | p.Leu443Ile | missense_variant | 4/7 | 1 | NM_000388.4 | P1 | |
CASR | ENST00000498619.4 | c.1327C>A | p.Leu443Ile | missense_variant | 4/7 | 1 | |||
CASR | ENST00000638421.1 | c.1327C>A | p.Leu443Ile | missense_variant | 4/7 | 5 | P1 | ||
CASR | ENST00000490131.7 | c.1327C>A | p.Leu443Ile | missense_variant | 3/5 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152200Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250360Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135322
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461670Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 10AN XY: 727138
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152200Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74370
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 17, 2021 | Variant summary: CASR c.1327C>A (p.Leu443Ile) results in a conservative amino acid change located in the Receptor, ligand binding region (IPR001828) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250360 control chromosomes, however, the available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1327C>A in individuals affected with Familial Hypocalciuric Hypercalcemia and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter has assessed this variant since 2014: it was classified as of uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Nephrolithiasis/nephrocalcinosis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 03, 2023 | The p.L443I variant (also known as c.1327C>A), located in coding exon 3 of the CASR gene, results from a C to A substitution at nucleotide position 1327. The leucine at codon 443 is replaced by isoleucine, an amino acid with highly similar properties. This alteration was identified in an individual from an international cohort of 478 pseudoxanthoma elasticum patients with ectopic mineralization; this individual is also noted to be compound heterozygous for alterations in ABCC6 (Saeidian AH et al. Genet Med, 2022 Jan;24:75-86). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 03, 2023 | This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 443 of the CASR protein (p.Leu443Ile). This variant is present in population databases (rs267599574, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with CASR-related conditions. ClinVar contains an entry for this variant (Variation ID: 410336). 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 tolerated. 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