Submissions for variant NM_000388.4(CASR):c.1619C>T (p.Ser540Phe)

dbSNP: rs1057518409

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414090	SCV000492014	uncertain significance	not specified	2016-11-15	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the CASR gene. The S540F variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It 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. S540F 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. Missense variants in nearby residues (E536D, C542R) have been reported in the Human Gene Mutation Database in association with hypocalciuric hypercalcemia (Stenson et al., 2014), supporting the functional importance of this region of the protein. However, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000414090	SCV001774707	uncertain significance	not specified	2023-09-28	criteria provided, single submitter	clinical testing	Variant summary: CASR c.1619C>T (p.Ser540Phe) results in a non-conservative amino acid change located in the GPCR, family 3, nine cysteines domain (IPR011500) 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 251490 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1619C>T in individuals affected with Familial Hypocalciuric Hypercalcemia and no experimental evidence demonstrating its impact on protein function have been reported. In the Human Gene Mutation Database (HGMD), there are several other missense variants (p.C542R, p.R544Q, p.C546G) affecting the nearby codons have been reported in association with Hypocalciuric Hypercalcaemia, suggesting the functional significance of this region. One ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV002524650	SCV003299203	uncertain significance	Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1	2022-01-15	criteria provided, single submitter	clinical testing	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. 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: 373422). This variant has not been reported in the literature in individuals affected with CASR-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 540 of the CASR protein (p.Ser540Phe).