Submissions for variant NM_000388.4(CASR):c.2489G>A (p.Gly830Asp)

dbSNP: rs193922436

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003387728	SCV000052094	uncertain significance	not specified	2023-09-22	criteria provided, single submitter	clinical testing	Variant summary: CASR c.2489G>A (p.Gly830Asp) results in a non-conservative amino acid change located in the GPCR family 3, C-terminal domain (IPR017978) 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 251008 control chromosomes (gnomAD). c.2489G>A has been reported in the literature in a woman and her father with mild hypocalcemia (example: Changcharoen_CASR_AACE Case report_2016). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: No Pubmed ID for Changcharoen_CASR_AACE Case report_2016 ). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Genetic Services Laboratory, University of Chicago	RCV001818185	SCV002067451	likely pathogenic	not provided	2020-03-19	criteria provided, single submitter	clinical testing	DNA sequence analysis of the CASR gene demonstrated a sequence change, c.2489G>A, in exon 7 that results in an amino acid change, p.Gly830Asp. The p.Gly830Asp change affects a highly conserved amino acid residue located in a transmembrane domain of the CASR protein that is known to be functional (PMID: 21645025). The p.Gly830Asp substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This particular amino acid change does not appear to have been described in the literature in other patients with CASR related disorders, however, a different sequence change affecting the same amino acid residue (p.Gly830Ser) has been described in patients with autosomal dominant hypoparathyroidism (ADH) (PMIDs: 21645025, 20668040, 20668040). This sequence change is absent from the large population databases like ExAC and gnomAD (dbSNP rs193922436). These collective evidences indicate that this sequence change is likely pathogenic; however functional studies have not been performed to prove this conclusively.