Submissions for variant NM_000388.4(CASR):c.1192G>A (p.Asp398Asn)

gnomAD frequency: 0.00052  dbSNP: rs201177696

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000054614	SCV000329202	uncertain significance	not provided	2016-03-09	criteria provided, single submitter	clinical testing	The D398N variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The NHLBI Exome Sequencing Project reports D398N was observed in 1/8600 (0.012%) alleles from individuals of European background, indicating it may be a rare variant in this population. The D398N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV001083262	SCV000561358	likely benign	Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1	2024-01-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002316208	SCV001170324	likely benign	Inborn genetic diseases; Nephrolithiasis/nephrocalcinosis	2018-12-07	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Genetic Services Laboratory, University of Chicago	RCV001818230	SCV002070991	uncertain significance	not specified	2018-06-18	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002255127	SCV002531527	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-23	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001818230	SCV004028643	likely benign	not specified	2023-07-14	criteria provided, single submitter	clinical testing	Variant summary: CASR c.1192G>A (p.Asp398Asn) results in a conservative amino acid change located in the Receptor, ligand binding region (IPR001828) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0006 in 251436 control chromosomes in gnomAD. The observed variant frequency is approximately 45-fold of the estimated maximal expected allele frequency for a pathogenic variant in CASR causing Familial Hypocalciuric Hypercalcemia phenotype (1.3e-05), strongly suggesting that the variant is benign. c.1192G>A has been reported in the literature in an individual affected with Familial Hypocalciuric Hypercalcemia. The variant was found to co-occur in this individual with a (likely) pathogenic variant (CASR c.1670G>A, p.Gly557Glu), providing supporting evidence for a benign role (Zajickova_2020). The following publication has been ascertained in the context of this evaluation (PMID: 33094630). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (Likely benign, n=2; Uncertain significance, n=3). Based on the evidence outlined above, the variant was classified as likely benign.
Martin Pollak Laboratory, Beth Israel Deaconess Medical Center	RCV000054614	SCV000077304	unknown	not provided		no assertion criteria provided	not provided	Converted during submission to Uncertain significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000054614	SCV001551647	uncertain significance	not provided		no assertion criteria provided	clinical testing	The CASR p.Asp398Asn variant was not identified in the literature but was identified in dbSNP (ID: rs201177696) and ClinVar (classified as uncertain significance by GeneDx and likely benign by Invitae and Ambry Genetics). The variant was identified in control databases in 147 of 268300 chromosomes at a frequency of 0.0005479 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: East Asian in 87 of 19250 chromosomes (freq: 0.004519), Ashkenazi Jewish in 10 of 9860 chromosomes (freq: 0.001014), Latino in 17 of 35106 chromosomes (freq: 0.000484), Other in 3 of 6702 chromosomes (freq: 0.000448) and European (non-Finnish) in 30 of 118132 chromosomes (freq: 0.000254), but was not observed in the African, European (Finnish), or South Asian populations. The p.Asp398 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.