rs1553768082
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3_Moderate
The ENST00000639785.2(CASR):c.1382T>A(p.Leu461Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. L461P) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000639785.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CASR | NM_000388.4 | c.1382T>A | p.Leu461Gln | missense_variant | 5/7 | ENST00000639785.2 | NP_000379.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CASR | ENST00000639785.2 | c.1382T>A | p.Leu461Gln | missense_variant | 5/7 | 1 | NM_000388.4 | ENSP00000491584 | P1 | |
CASR | ENST00000498619.4 | c.1382T>A | p.Leu461Gln | missense_variant | 5/7 | 1 | ENSP00000420194 | |||
CASR | ENST00000638421.1 | c.1382T>A | p.Leu461Gln | missense_variant | 5/7 | 5 | ENSP00000492190 | P1 | ||
CASR | ENST00000490131.7 | c.1378-6297T>A | intron_variant | 5 | ENSP00000418685 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
CASR-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 02, 2022 | The CASR c.1382T>A variant is predicted to result in the amino acid substitution p.Leu461Gln. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. A different amino acid substitution as this position (p.Leu461Gln) has been reported in two individuals with familial hypocalciuric hypercalcemia (Hannan et al 2012. PubMed ID: 22422767). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 15, 2017 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with CASR-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with glutamine at codon 461 of the CASR protein (p.Leu461Gln). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and glutamine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at