3-122254191-T-C

Position:

• chr3-122254191-T-C

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_000388.4(CASR):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: CASR NM_000388.4 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.23

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 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_000388.4 (CASR) was described as [Pathogenic] in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-122254191-T-C is Pathogenic according to our data. Variant chr3-122254191-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2035301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASR	NM_000388.4	c.2T>C	p.Met1?	start_lost	2/7	ENST00000639785.2	NP_000379.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASR	ENST00000639785.2	c.2T>C	p.Met1?	start_lost	2/7	1	NM_000388.4	ENSP00000491584.2
CASR	ENST00000498619.4	c.2T>C	p.Met1?	start_lost	2/7	1		ENSP00000420194.1
CASR	ENST00000638421.1	c.2T>C	p.Met1?	start_lost	2/7	5		ENSP00000492190.1
CASR	ENST00000490131.7	c.2T>C	p.Met1?	start_lost	1/5	5		ENSP00000418685.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152182 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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74354

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: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2022

Disruption of the initiator codon has been observed in individual(s) with clinical features of autosomal recessive neonatal severe hyperparathyroidism (PMID: 17121537). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the CASR protein in which other variant(s) (p.Pro55Leu) have been determined to be pathogenic (PMID: 8675635, 8878438, 12580936, 19389809). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Experimental studies have shown that disruption of the initiator codon affects CASR function (PMID: 17121537). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the CASR mRNA. The next in-frame methionine is located at codon 74. -

Familial hypocalciuric hypercalcemia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Sep 26, 2023

Variant summary: CASR c.2T>C (p.Met1?) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The next in-frame Methionine is located at codon 74 (c.220 to c.222) in exon 3 of the coding sequence. Other pathogenic variants upstream of this location have been classified as pathogenic in association with Familial Hypocalciuric Hypercalcemia (FHH) or Neonatal Severe Hyperparathyroidism (NSHPT) by our laboratory (example, c.206G>A, p.Arg69His, c.164C>T, p.Pro55Leu and c.157T>C, p.Ser53Pro) supporting a critical relevance of this domain for overall protein function. The variant was absent in 251304 control chromosomes. To our knowledge, no occurrence of c.2T>C in individuals affected with Familial Hypocalciuric Hypercalcemia/Neonatal Severe Hyperparathyroidism and no experimental evidence demonstrating its impact on protein function have been reported. One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.27
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.42	T;T;.;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	.;D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.22	D
PROVEAN	Benign	-1.3	.;.;N;N
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0010	.;.;D;D
Sift4G	Uncertain	0.0030	.;.;D;D
Polyphen		0.46	P;P;.;.
Vest4		0.83, 0.86
MutPred		0.84		Loss of glycosylation at S5 (P = 0.0332);Loss of glycosylation at S5 (P = 0.0332);Loss of glycosylation at S5 (P = 0.0332);Loss of glycosylation at S5 (P = 0.0332);
MVP		0.94
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.75
gMVP		0.83

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: rs1467887809; hg19: chr3-121973038;