Submissions for variant NM_000388.4(CASR):c.1913G>T (p.Arg638Leu)

dbSNP: rs201852643

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255744	SCV000322405	pathogenic	not provided	2016-05-23	criteria provided, single submitter	clinical testing	The R638L missense variant in the CASR gene has been reported previously in association with calcium homeostasis disorders (D'Souza-Li et al., 2002; Corrado et al., 2015). The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. R638L is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Functional studies have shown that R638L prevents proper localization of the CASR protein and results in its degradation (White et al., 2009). Therefore, this variant is pathogenic.
Invitae	RCV001855012	SCV002291417	uncertain significance	Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1	2023-08-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 638 of the CASR protein (p.Arg638Leu). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism (PMID: 25828954, 26963950). ClinVar contains an entry for this variant (Variation ID: 265466). 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: 19389809). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317177	SCV004020596	uncertain significance	not specified	2023-06-06	criteria provided, single submitter	clinical testing	Variant summary: CASR c.1913G>T (p.Arg638Leu) results in a non-conservative amino acid change located in the C-terminal cytoplasmic domain (IPR17978) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251328 control chromosomes( i.e. in 1 carrier) in the gnomAD database (v2.1). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.1913G>T, has been reported in the literature in a compound heterozygous individual affected with Neonatal Severe Hyperparathyroidism, and in heterozygous state in one of her parents, affected with Familial Hypocalciuric Hypercalcemia (Corrado_2015); in addition, the variant was also reported in a cohort of patients affected with Familial Hypocalciuric Hypercalcemia (Vargas-Poussou_2016). At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant prevented proper localization of the CASR protein at the plasma membrane, and likely resulted in its degradation in the endoplasmic reticulum (White_2009). The following publications have been ascertained in the context of this evaluation (PMID: 19389809, 26963950, 25828954). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. One laboratory classified the variant as pathogenic, while the other laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.