Submissions for variant NM_000388.4(CASR):c.2405A>G (p.Asn802Ser)

gnomAD frequency: 0.00001  dbSNP: rs140022350

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000433842	SCV000517455	pathogenic	not provided	2015-06-15	criteria provided, single submitter	clinical testing	The N802S missense variant in the CASR gene has been reported previously in association with familialhypercalciuric hypocalcemia in a female patient with milder phenotype (Lia-Baldini et al., 2013). N802Swas not observed at any significant frequency in approximately 6,500 individuals of European and AfricanAmerican ancestry by the NHLBI Exome Sequencing Project. It is a conservative amino acid substitution,which is not likely to impact secondary protein structure as these residues share similar properties. Thissubstitution occurs at a position where amino acids with similar properties to asparagine are toleratedacross species. In silico analysis predicts this variant is probably damaging to the protein structure/function.In addition, missense variants at the same codon (N802I) and in nearby residues (R795W, P798T/L,E799K, N800T, A804D, F806S/L, M811V) have been reported in the Human Gene Mutation Database inassociation with CASR-related disorders (Stenson et al., 2014), supporting the functional importance of thisregion of the protein. Therefore, we consider N802S to be a pathogenic variant.
Invitae	RCV000700033	SCV000828769	likely pathogenic	Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1	2023-11-15	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 802 of the CASR protein (p.Asn802Ser). This variant is present in population databases (rs140022350, gnomAD 0.01%). This missense change has been observed in individual(s) with familial hypocalciuric hypercalcemia (PMID: 23169696, 26963950, 32386559). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 379931). 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: 23169696, 32386559). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000433842	SCV001250023	pathogenic	not provided	2016-09-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002488902	SCV002811625	likely pathogenic	Familial hypocalciuric hypercalcemia 1; Neonatal severe primary hyperparathyroidism; Epilepsy, idiopathic generalized, susceptibility to, 8; Autosomal dominant hypocalcemia 1	2021-12-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003993953	SCV004813572	likely pathogenic	Familial hypocalciuric hypercalcemia	2024-02-26	criteria provided, single submitter	clinical testing	Variant summary: CASR c.2405A>G (p.Asn802Ser) results in a conservative amino acid change located in the GPCR family 3, C-terminal domain (IPR017978) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 1614010 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CASR causing Familial Hypocalciuric Hypercalcemia (8.1e-06 vs 1.3e-05), allowing no conclusion about variant significance. c.2405A>G has been reported in the literature in individuals affected with Familial Hypocalciuric Hypercalcemia (e.g. Lia-Baldini_2013, Vargas-Poussou_2016, Dershem_2020). These data indicate that the variant is likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function (e.g. Lia-Baldini_2013, Dershem_2020). The variant was found to have reduced plasma membrane localization and a response to extracellular calcium that was approximately 50% of the WT protein. The following publications have been ascertained in the context of this evaluation (PMID: 26963950, 32386559, 23169696). ClinVar contains an entry for this variant (Variation ID: 379931). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV004554774	SCV005044013	pathogenic	CASR-related disorder	2024-01-23	criteria provided, single submitter	clinical testing	PS3, PM1, PM2, PM5_Supporting, PP2