chr3-122261883-T-C

Position:

• chr3-122261883-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PP2 PP5 BS1_Supporting

The NM_000388.4(CASR):​c.848T>C​(p.Ile283Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000681 in 1,614,100 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000068 (1 hom.)
• Consequence: CASR NM_000388.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:10
• Conservation: PhyloP100: 8.02

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 Uncertain_significance. Variant got 1 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CASR. . Gene score misZ 3.1237 (greater than the threshold 3.09). Trascript score misZ 4.8257 (greater than threshold 3.09). GenCC has associacion of gene with epilepsy, autosomal dominant hypocalcemia, familial hypocalciuric hypercalcemia 1, epilepsy, idiopathic generalized, susceptibility to, 8, neonatal severe primary hyperparathyroidism, autosomal dominant hypocalcemia 1.
• PP5: Variant 3-122261883-T-C is Pathogenic according to our data. Variant chr3-122261883-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 410355.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=8, Pathogenic=2}. Variant chr3-122261883-T-C is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000677 (99/1461894) while in subpopulation MID AF= 0.00121 (7/5768). AF 95% confidence interval is 0.000569. There are 1 homozygotes in gnomad4_exome. There are 45 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASR	NM_000388.4	c.848T>C	p.Ile283Thr	missense_variant	4/7	ENST00000639785.2	NP_000379.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASR	ENST00000639785.2	c.848T>C	p.Ile283Thr	missense_variant	4/7	1	NM_000388.4	ENSP00000491584	P1
CASR	ENST00000498619.4	c.848T>C	p.Ile283Thr	missense_variant	4/7	1		ENSP00000420194
CASR	ENST00000638421.1	c.848T>C	p.Ile283Thr	missense_variant	4/7	5		ENSP00000492190	P1
CASR	ENST00000490131.7	c.848T>C	p.Ile283Thr	missense_variant	3/5	5		ENSP00000418685

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000103 AC: 26 AN: 251332 Hom.: 0 AF XY: 0.0000810 AC XY: 11 AN XY: 135858

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000677 AC: 99 AN: 1461894 Hom.: 1 Cov.: 34 AF XY: 0.0000619 AC XY: 45 AN XY: 727248

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000728

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74366

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000138 Hom.: 0

Bravo AF: 0.0000869

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.0000545

EpiControl AF: 0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 04, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 20, 2023	PP2, PS4_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 15, 2015	The I283T missense variant in the CASR gene has been reported previously in association with a CASR-related disorder (Guarnieri et al., 2010). Functional analysis showed impaired maturation, cell surface expression, and signaling of the I283T mutant protein compared with wild type. We interpret the I283T variant as pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 28, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2016	- -

Familial hypocalciuric hypercalcemia 1 Pathogenic:1 Uncertain:1

Uncertain significance, no assertion criteria provided	clinical testing	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	Nov 08, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 03, 2023	Variant summary: CASR c.848T>C (p.Ile283Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 251332 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CASR causing Familial Hypocalciuric Hypercalcemia (0.0001 vs 0.005), allowing no conclusion about variant significance. c.848T>C has been reported in the literature in at least one heterozygous individual affected with primary hyperparathyroidism (e.g. Guarnieri_2010). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hypocalciuric Hypercalcemia. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (e.g.Guarnieri_2010). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=6) or pathogenic (n=2). 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

Dec 05, 2023

The p.I283T variant (also known as c.848T>C), located in coding exon 3 of the CASR gene, results from a T to C substitution at nucleotide position 848. The isoleucine at codon 283 is replaced by threonine, an amino acid with similar properties. This variant has been detected in an individual with primary hyperparathyroidism and reported to impair cell surface expression and signaling (Guarnieri V et al. J. Clin. Endocrinol. Metab., 2010 Apr;95:1819-29). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

CASR-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 05, 2024

The CASR c.848T>C variant is predicted to result in the amino acid substitution p.Ile283Thr. This variant was reported in a 56-year-old woman with primary hyperparathyroidism (PHPT); functional analysis showed that this variant impaired the protein maturation, cell surface expression, and signaling (Guarnieri et al. 2010. PubMed ID: 20164288) and in an individual with kidney stone disease (Table S1, Anderegg et al. 2023. https://www.medrxiv.org/content/10.1101/2023.07.23.23292924v2.full). This variant is reported in 0.017% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, its clinical significance 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

Dec 28, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 283 of the CASR protein (p.Ile283Thr). This variant is present in population databases (rs142745096, gnomAD 0.02%). This missense change has been observed in individual(s) with primary hyperparathyroidism (PMID: 20164288). ClinVar contains an entry for this variant (Variation ID: 410355). 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. Experimental studies have shown that this missense change affects CASR function (PMID: 20164288). 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. -

See cases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Mar 21, 2022

ACMG categories: PM2,PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D;D;.;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	.;D;D;D
M_CAP	Benign	0.084	D
MetaRNN	Uncertain	0.72	D;D;D;D
MetaSVM	Uncertain	-0.0031	T
MutationAssessor	Benign	1.3	L;L;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.1	.;.;D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0030	.;.;D;D
Sift4G	Uncertain	0.028	.;.;D;D
Polyphen		0.92	P;P;.;.
Vest4		0.94, 0.94
MVP		0.98
MPC		1.6
ClinPred		0.30	T
GERP RS		6.2
Varity_R		0.76
gMVP		0.69

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: rs142745096; hg19: chr3-121980730;