Submissions for variant NM_000388.4(CASR):c.1742C>T (p.Ala581Val)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004788438	SCV005400358	likely pathogenic	Familial hypocalciuric hypercalcemia 1	2024-09-21	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with hypocalciuric hypercalcaemia (MIM#145980) and neonatal hyperparathyroidism (MIM#239200). Gain of function is associated with hypocalcaemia, with or without Bartter syndrome (MIM#601198) (PMID: 22422767, 26646938). (I) 0108 - This gene is associated with both recessive and dominant disease. (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. Intrafamilial variability has been reported (PMID: 11807402). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Labcorp Genetics (formerly Invitae), Labcorp	RCV005218314	SCV005857422	likely pathogenic	Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1	2024-09-16	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 581 of the CASR protein (p.Ala581Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypocalciuric hypercalcemia (internal data). In at least one individual the variant was observed to be de novo. 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. 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.