NM_000388.4(CASR):c.1192G>A (p.Asp398Asn) AND not provided

Clinical significance:Uncertain significance (Last evaluated: Mar 9, 2016)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000054614.5

Allele description [Variation Report for NM_000388.4(CASR):c.1192G>A (p.Asp398Asn)]

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

Gene:
CASR:calcium sensing receptor [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
3q21.1
Genomic location:
Preferred name:
NM_000388.4(CASR):c.1192G>A (p.Asp398Asn)
HGVS:
  • NC_000003.12:g.122262227G>A
  • NG_009058.1:g.83545G>A
  • NM_000388.4:c.1192G>AMANE SELECT
  • NM_001178065.2:c.1192G>A
  • NP_000379.3:p.Asp398Asn
  • NP_001171536.2:p.Asp398Asn
  • NC_000003.11:g.121981074G>A
  • NM_000388.3:c.1192G>A
Protein change:
D398N
Links:
dbSNP: rs201177696
NCBI 1000 Genomes Browser:
rs201177696
Molecular consequence:
  • NM_000388.4:c.1192G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001178065.2:c.1192G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000077304Martin Pollak Laboratory, Beth Israel Deaconess Medical Centerno assertion criteria providedunknownnot providednot provided

SCV000329202GeneDxcriteria provided, single submitter
Uncertain significance
(Mar 9, 2016)
germlineclinical testing

Citation Link,

SCV001551647Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria providedUncertain significanceunknownclinical testing

Description

Lower UCa2+ group

SCV000077304

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providednot providednot providednot providednot providednot provided1not providedliterature only

Details of each submission

From Martin Pollak Laboratory, Beth Israel Deaconess Medical Center, SCV000077304.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providednot providednot provided

Description

Converted during submission to Uncertain significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1not providednot provided1not providednot providednot providednot providednot providednot provided

From GeneDx, SCV000329202.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001551647.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 23, 2021

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