Submissions for variant NM_000388.4(CASR):c.428G>A (p.Gly143Glu)

dbSNP: rs121909264

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Molecular Diagnostics Lab, Nemours Children's Health, Delaware	RCV000498830	SCV000590873	pathogenic	not provided	2015-12-30	criteria provided, single submitter	clinical testing
Invitae	RCV000549803	SCV000638075	pathogenic	Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1	2023-12-05	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 143 of the CASR protein (p.Gly143Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial hypocalciuric hypercalcemia (FHH) (PMID: 1302026, 7726161, 26963950). It has also been observed to segregate with disease in related individuals. This variant is also known as Gly144Glu. ClinVar contains an entry for this variant (Variation ID: 8333). 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: 8702647, 10077597, 12095982, 12114500, 12890593, 19389809, 23077345). This variant disrupts the p.Gly143 amino acid residue in CASR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19179454, 32347971; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271366	SCV002556052	pathogenic	Familial hypocalciuric hypercalcemia	2022-06-02	criteria provided, single submitter	clinical testing	Variant summary: CASR c.428G>A (p.Gly143Glu) results in a non-conservative amino acid change located in the Receptor, ligand binding region of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251406 control chromosomes. c.428G>A has been reported in the literature in multiple individuals affected with Familial Hypocalciuric Hypercalcemia (examples: Chou_1992, Chou_1995, Vargas-Poussou_2016, etc). At least one publication reports the variant to lead to defective localization to plasma membrane compared to WT (White_2009). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000008835	SCV000029045	pathogenic	Familial hypocalciuric hypercalcemia 1	1995-05-01	no assertion criteria provided	literature only