rs1057521129

Variant names:

• chr3-122284385-A-G
• rs1057521129
• NM_000388.4:c.2431A>G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_000388.4(CASR):​c.2431A>G​(p.Met811Val) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CASR NM_000388.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 9.32

Genes affected

CASR (HGNC:1514): (calcium sensing receptor) The protein encoded by this gene is a plasma membrane G protein-coupled receptor that senses small changes in circulating calcium concentration. The encoded protein couples this information to intracellular signaling pathways that modify parathyroid hormone secretion or renal cation handling, and thus this protein plays an essential role in maintaining mineral ion homeostasis. Mutations in this gene are a cause of familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a helix (size 17) in uniprot entity CASR_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_000388.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the CASR gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 114 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 3.1237 (above the threshold of 3.09). Trascript score misZ: 4.8257 (above the threshold of 3.09). GenCC associations: The gene is linked to epilepsy, autosomal dominant hypocalcemia, familial hypocalciuric hypercalcemia 1, epilepsy, idiopathic generalized, susceptibility to, 8, neonatal severe primary hyperparathyroidism, autosomal dominant hypocalcemia 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975
• PP5: Variant 3-122284385-A-G is Pathogenic according to our data. Variant chr3-122284385-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 381654.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}. Variant chr3-122284385-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASR	NM_000388.4	c.2431A>G	p.Met811Val	missense_variant	Exon 7 of 7	ENST00000639785.2	NP_000379.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASR	ENST00000639785.2	c.2431A>G	p.Met811Val	missense_variant	Exon 7 of 7	1	NM_000388.4	ENSP00000491584.2
CASR	ENST00000498619.4	c.2461A>G	p.Met821Val	missense_variant	Exon 7 of 7	1		ENSP00000420194.1
CASR	ENST00000638421.1	c.2431A>G	p.Met811Val	missense_variant	Exon 7 of 7	5		ENSP00000492190.1
CASR	ENST00000490131.7	c.2200A>G	p.Met734Val	missense_variant	Exon 5 of 5	5		ENSP00000418685.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 70

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Apr 05, 2017

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The M811V variant in the CASR gene has been reported previously in an individual with epilepsy and hypocalcaemia; the variant was shown to segregate with the hypocalcaemic phenotype in three generations of affected individuals in this family, while unaffected family members were negative for the variant (Schouten et al., 2011). The M811V variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The M811V variant is a conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The M811V variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. -

Autosomal dominant hypocalcemia Pathogenic:1

Dec 16, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CASR c.2431A>G (p.Met811Val) results in a conservative amino acid change located in the G-protein coupled receptors family 3 (IPR017978) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.2431A>G has been reported in the literature in individuals affected with hypoparathyroidism (Schouten_2011, Schouten_2011, Klee_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29375828, 33144682, 21441391). ClinVar contains an entry for this variant (Variation ID: 381654). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia Uncertain:1

Oct 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 811 of the CASR protein (p.Met811Val). This missense change has been observed in individual(s) with autosomal dominant hypocalcemia (PMID: 21441391, 29375828). ClinVar contains an entry for this variant (Variation ID: 381654). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;D;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	H;H;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.7	.;.;D;N
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0020	.;.;D;T
Sift4G	Uncertain	0.0030	.;.;D;.
Polyphen		0.98	D;D;.;.
Vest4		0.96
MutPred		0.90		.;.;Gain of catalytic residue at M821 (P = 0.1015);.;
MVP		0.96
MPC		1.6
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.88
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1057521129; hg19: chr3-122003232;