ClinVar Miner

Submissions for variant NM_000388.4(CASR):c.1192G>A (p.Asp398Asn) (rs201177696)

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Total submissions: 5
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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; Hypocalcemia, autosomal dominant 1 2020-11-20 criteria provided, single submitter clinical testing
Ambry Genetics RCV001010168 SCV001170324 likely benign Inborn genetic diseases 2018-12-07 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
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.

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