VCV002573018.2 - ClinVar

NM_000388.4(CASR):c.372C>G (p.Asn124Lys)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(2)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000388.4(CASR):c.372C>G (p.Asn124Lys)

Variation ID: 2573018 Accession: VCV002573018.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3q21.1 3: 122257267 (GRCh38) [ NCBI UCSC ] 3: 121976114 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jul 22, 2023	Feb 28, 2024	Feb 17, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000388.4:c.372C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000379.3:p.Asn124Lys	missense
NM_001178065.2:c.372C>G	NP_001171536.2:p.Asn124Lys	missense
NC_000003.12:g.122257267C>G
NC_000003.11:g.121976114C>G
NG_009058.2:g.78600C>G

... more HGVS ... less HGVS

Protein change

N124K

Other names

Canonical SPDI

NC_000003.12:122257266:C:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CASR		No evidence available	No evidence available	GRCh38 GRCh37	2740	2763

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Autosomal dominant hypocalcemia 1	Likely pathogenic (1)	criteria provided, single submitter	Feb 17, 2023	RCV003315132.1
Autosomal dominant hypocalcemia 1 Familial hypocalciuric hypercalcemia	Uncertain significance (1)	criteria provided, single submitter	Jan 16, 2023	RCV003777287.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Feb 17, 2023)	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020) Method: clinical testing	Autosomal dominant hypocalcemia 1 Affected status: unknown Allele origin: unknown	Illumina Laboratory Services, Illumina Accession: SCV004014750.1 First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023	Publications: PubMed (4) PubMed: 12162500‚ 21441391‚ 24244430‚ 35818129 Comment: The CASR c.372C>G (p.Asn124Lys) missense variant results in the substitution of asparagine at amino acid position 124 with lysine. A different nucleotide change resulting in … (more) The CASR c.372C>G (p.Asn124Lys) missense variant results in the substitution of asparagine at amino acid position 124 with lysine. A different nucleotide change resulting in the same amino acid change, c.372C>A (p.Asn124Lys), has been reported in three symptomatic individuals with autosomal dominant hypocalcemia from two unrelated families (PMID: 12162500; PMID: 21441391). This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. The p.Asn124Lys variant is located in loop 2 of the extracellular domain, which is involved in ligand binding, in close proximity to other reported disease-causing missense variants (PMID: 35818129). Functional studies performed in HEK-293 cells indicate that p.Asn124Lys confers an increased sensitivity to external calcium and increased retention of calcium in the endoplasmic reticulum when compared to wild-type (PMID: 12162500; PMID: 24244430). Based on the available evidence, the c.372C>G (p.Asn124Lys) variant is classified as a likely pathogenic for autosomal dominant hypocalcemia. (less)
Uncertain significance (Jan 16, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Familial hypocalciuric hypercalcemia Autosomal dominant hypocalcemia 1 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004585068.1 First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024	Publications: PubMed (3) PubMed: 12162500‚ 24244430‚ 21441391 Comment: 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 … (more) 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. Experimental studies have shown that this missense change affects CASR function (PMID: 12162500, 24244430). 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. This missense change has been observed in individual(s) with autosomal dominant hypocalcemia (PMID: 12162500, 21441391). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 124 of the CASR protein (p.Asn124Lys). (less)

Comment:

The CASR c.372C>G (p.Asn124Lys) missense variant results in the substitution of asparagine at amino acid position 124 with lysine. A different nucleotide change resulting in the same amino acid change, c.372C>A (p.Asn124Lys), has been reported in three symptomatic individuals with autosomal dominant hypocalcemia from two unrelated families (PMID: 12162500; PMID: 21441391). This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. The p.Asn124Lys variant is located in loop 2 of the extracellular domain, which is involved in ligand binding, in close proximity to other reported disease-causing missense variants (PMID: 35818129). Functional studies performed in HEK-293 cells indicate that p.Asn124Lys confers an increased sensitivity to external calcium and increased retention of calcium in the endoplasmic reticulum when compared to wild-type (PMID: 12162500; PMID: 24244430). Based on the available evidence, the c.372C>G (p.Asn124Lys) variant is classified as a likely pathogenic for autosomal dominant hypocalcemia.

Comment:

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. Experimental studies have shown that this missense change affects CASR function (PMID: 12162500, 24244430). 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. This missense change has been observed in individual(s) with autosomal dominant hypocalcemia (PMID: 12162500, 21441391). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 124 of the CASR protein (p.Asn124Lys).

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Autosomal dominant hypocalcemia with a novel CASR mutation: a case study and literature review.	Wu Y	The Journal of international medical research	2022	PMID: 35818129
Excessive signal transduction of gain-of-function variants of the calcium-sensing receptor (CaSR) are associated with increased ER to cytosol calcium gradient.	Ranieri M	PloS one	2013	PMID: 24244430
Four cases of autosomal dominant hypocalcaemia with hypercalciuria including two with novel mutations in the calcium-sensing receptor gene.	Schouten BJ	Annals of clinical biochemistry	2011	PMID: 21441391
Autosomal dominant hypocalcemia caused by a novel mutation in the loop 2 region of the human calcium receptor extracellular domain.	Hu J	Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research	2002	PMID: 12162500

Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_000388.4(CASR):c.372C>G (p.Asn124Lys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...