Submissions for variant NM_000388.4(CASR):c.1810G>A (p.Glu604Lys)

dbSNP: rs104893712

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414467	SCV000490453	pathogenic	not provided	2015-08-25	criteria provided, single submitter	clinical testing	The E604K missense variant in the CASR gene has been reported previously in autosomal dominant hypocalcemia (Tan et al., 2003; Alvarez-Hernández et al., 2003; Winer et al., 2014). E604K is a non-conservative amino acid substitution as a negatively charged Glutamic Acid residue is replaced with a positively charged Lysine residue. In vivo functional studies have shown that E604K is an activating variant, enhancing the receptor's extracellular calcium sensitivity (Tan et al., 2003). Therefore, we interpret E604K as a pathogenic variant.
Athena Diagnostics Inc	RCV000414467	SCV000612654	pathogenic	not provided	2021-07-22	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant appears to segregate with disease in at least one family. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant decreased the response of the receptor to calcium (PMID: 12574188).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001804717	SCV002051300	pathogenic	Autosomal dominant hypocalcemia	2021-12-01	criteria provided, single submitter	clinical testing	Variant summary: CASR c.1810G>A (p.Glu604Lys) 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 was absent in 251472 control chromosomes. c.1810G>A has been reported in the literature in multiple individuals affected with Autosomal Dominant Hypocalcemia, including 2 families where the variant segregated with the disease (Tan_2003, Alvarez-Hernandez_2003). These data indicate that the variant is very likely to be associated with disease. To our knowledge, least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in approximately 60% of normal activity. Three ClinVar submitters have classified this variant (after 2014) as pathogenic . Based on the evidence outlined above, the variant was classified as pathogenic.
Genetic Services Laboratory, University of Chicago	RCV000414467	SCV002067499	pathogenic	not provided	2020-06-22	criteria provided, single submitter	clinical testing	DNA sequence analysis of the CASR gene demonstrated a sequence change, c.1810G>A, in exon 7 that results in an amino acid change, p.Glu604Lys. This sequence change has not been described in the large population databases such as ExAC and gnomAD (dbSNP rs104893712). This sequence change has previously been described in families with autosomal dominant hypocalcemia (PMID: 12574188) and hypoparathyroidism (PMIDs: 14519094,24948345). The p.Glu604Lys change affects a highly conserved amino acid residue located in a cysteine-rich domain of the extracellular head (PMID: 17039419, 14519094) and is classified as an activating mutation. Functional studies have suggested that this variant significantly increases the extracellular Ca2+ sensitivity of the receptor in vivo (PMID: 12574188). The p.Glu604Lys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). These collective evidences indicate that this sequence change is pathogenic.
Invitae	RCV001851749	SCV002194966	pathogenic	Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1	2022-09-12	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CASR function (PMID: 12574188). 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. ClinVar contains an entry for this variant (Variation ID: 8350). This missense change has been observed in individual(s) with hypocalcemia and/or hypoparathyroidism (PMID: 12574188, 14519094, 24948345). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 604 of the CASR protein (p.Glu604Lys).
Ambry Genetics	RCV003343599	SCV004065986	pathogenic	Nephrolithiasis/nephrocalcinosis	2023-09-11	criteria provided, single submitter	clinical testing	The c.1810G>A (p.E604K) alteration is located in exon 7 (coding exon 6) of the CASR gene. This alteration results from a G to A substitution at nucleotide position 1810, causing the glutamic acid (E) at amino acid position 604 to be replaced by a lysine (K). Based on the available evidence, the CASR c.1810G>A (p.E604K) alteration is classified as pathogenic for autosomal dominant CASR-related hypocalcemia; however, it is unlikely to be causative of autosomal recessive neonatal hyperparathyroidism and autosomal dominant hypocalciuric hypercalcemia. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been detected in the heterozygous state in multiple individuals with CASR-related hypocalcemia and cosegregates with disease in several families (Ovejero, 2019; Winer, 2018; Hannan, 2012; Tan, 2003; Alvarez-Hernández, 2003). In addition, this variant has been determined to be the result of a de novo mutation in one individual with features consistent with CASR-related hypocalcemia (Qin, 2022). This amino acid position is highly conserved in available vertebrate species. In vitro functional studies showed that this variant increases the sensitivity to extracellular calcium (Tan, 2003; Cavaco, 2018). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003390663	SCV004119650	pathogenic	CASR-related condition	2023-12-19	criteria provided, single submitter	clinical testing	The CASR c.1840G>A variant is predicted to result in the amino acid substitution p.Glu614Lys. This variant was reported to cause autosomal dominant hypocalcemia (reported as E604K in Tan et al. 2003. PubMed ID: 12574188; Hannan FM et al 2012. PubMed ID: 22422767). This variant was also reported in two patients with hypoparathyroidism (also reported as E604K in Patients G and H in Winer et al. 2014. PubMed ID: 24948345). In the Tan et al. study, this variant co-segregated with disease in a family, and functional studies showed that the p.Glu614Lys change enhances the extracellular Ca2+ sensitivity of the calcium-sensing receptor (CaR). This variant has not been reported in a large population database, indicating it is rare. This variant is interpreted as pathogenic.
OMIM	RCV000008855	SCV000029065	pathogenic	Autosomal dominant hypocalcemia 1	2003-02-01	no assertion criteria provided	literature only
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000008855	SCV001468194	pathogenic	Autosomal dominant hypocalcemia 1	2020-07-02	no assertion criteria provided	clinical testing