Submissions for variant NM_000388.4(CASR):c.32T>C (p.Leu11Ser)

gnomAD frequency: 0.00004  dbSNP: rs200673016

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000802402	SCV000942233	uncertain significance	Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1	2024-11-05	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 11 of the CASR protein (p.Leu11Ser). This variant is present in population databases (rs200673016, gnomAD 0.003%). This missense change has been observed in individual(s) with primary hyperparathyroidism (HPT) (PMID: 15879434). ClinVar contains an entry for this variant (Variation ID: 647813). 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 tolerated. Experimental studies have shown that this missense change affects CASR function (PMID: 15879434). 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.
Illumina Laboratory Services, Illumina	RCV001146802	SCV001307561	uncertain significance	Familial hypoparathyroidism	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001146803	SCV001307562	uncertain significance	Autosomal dominant hypocalcemia 1	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001146804	SCV001307563	uncertain significance	Neonatal severe primary hyperparathyroidism	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001147690	SCV001308531	uncertain significance	Familial hypocalciuric hypercalcemia 1	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Ambry Genetics	RCV004028108	SCV002611236	uncertain significance	Nephrolithiasis/nephrocalcinosis	2023-08-15	criteria provided, single submitter	clinical testing	The p.L11S variant (also known as c.32T>C), located in coding exon 1 of the CASR gene, results from a T to C substitution at nucleotide position 32. The leucine at codon 11 is replaced by serine, an amino acid with dissimilar properties. This variant was detected in an individual with primary hyperparathyroidism and hypercalcemia, and it was reported in two affected siblings; in vitro studies indicated that this alteration may impact protein function (Pidasheva S et al. Hum Mol Genet, 2005 Jun;14:1679-90). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002507390	SCV002814408	uncertain significance	Familial hypocalciuric hypercalcemia 1; Neonatal severe primary hyperparathyroidism; Epilepsy, idiopathic generalized, susceptibility to, 8; Autosomal dominant hypocalcemia 1	2024-04-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004702431	SCV005205488	uncertain significance	not specified	2024-06-25	criteria provided, single submitter	clinical testing	Variant summary: CASR c.32T>C (p.Leu11Ser) results in a non-conservative amino acid change located in the signal peptide hydrophobic core (PMID: 15879434) of 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 251340 control chromosomes (gnomAD). c.32T>C has been reported in the literature in at least an individual affected with Familial Hypocalciuric Hypercalcemia (example: Pidasheva_2005). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hypocalciuric Hypercalcemia. In in vitro functional studies, the variant failed to be inserted in the microsomes and undergo glycosylation (Pidasheva_2005). The following publication has been ascertained in the context of this evaluation (PMID: 15879434). ClinVar contains an entry for this variant (Variation ID: 647813). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV004792491	SCV005410365	uncertain significance	not provided	2024-08-21	criteria provided, single submitter	clinical testing	PP2, PM2, PS3_supporting