ClinVar Miner

Submissions for variant NM_032119.4(ADGRV1):c.11974G>A (p.Asp3992Asn) (rs201386977)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000155111 SCV000204797 likely benign not specified 2013-03-14 criteria provided, single submitter clinical testing p.Asp3992Asn in exon 58 of GPR98: This variant is not expected to have clinical significance because it has been identified in 0.4% (59/15416) of European chrom osomes and in 0.4% (4/944) of Latino chromosomes by the Exome Aggregation Consor tium (http://exac.broadinstitute.org/; dbSNP rs201386977).
GeneDx RCV000155111 SCV000321754 uncertain significance not specified 2017-05-11 criteria provided, single submitter clinical testing The D3992N variant in the ADGRV1 gene has been reported previously in an individual with Usher syndrome who also harbored a nonsense variant in the ADGRV1 gene, although parental studies were not performed to determine the phase of these two variants (Bonnet et al., 2016). The D3992N variant has also been reported in individuals with features suggestive of Usher syndrome but without a second disease causing variant in the ADGRV1 gene identified (Licastro et al., 2012; Aparisi et al., 2014). The D3922N is observed in 59/15,416 (0.38%) alleles from individuals of non-Finnish European background in the ExAC dataset (Lek et al., 2016). Additionally, this variant has been observed in the homozygous state in two unrelated, presumably healthy individuals tested at GeneDx. The D3992N 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 conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret D3992N as a variant of uncertain significance.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000585241 SCV000345478 uncertain significance not provided 2016-09-12 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000585241 SCV000693179 uncertain significance not provided 2020-01-01 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000585241 SCV000840638 uncertain significance not provided 2018-04-26 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000585241 SCV000884985 uncertain significance not provided 2017-10-03 criteria provided, single submitter clinical testing The p.Asp3992Asn variant (rs201386977) has been reported in the medical literature in several individuals with Usher syndrome; however, inheritance and specific clinical information were not reported (Aparisi 2014, Bonnet 2016, and Licastro 2012). The p.Asp3992Asn variant is listed in the Genome Aggregation Database (gnomAD) browser with an overall allele frequency of 0.14% (identified in 313 out of 225,132 chromosomes), and found in ClinVar with conflicting interpretations of pathogenicity (Variant ID: 178365). The aspartic acid at codon 3992 is highly conserved considering 12 species up to zebrafish (Alamut software v2.10.0), and computational analyses suggest that this variant affects the structure/function of the ADGRV1 protein (SIFT: damaging, PolyPhen2: probably damaging, MutationTaster: disease causing). However, based on the available information, the clinical significance of the p.Asp3992Asn variant cannot be determined with certainty.
Invitae RCV000585241 SCV001038889 likely benign not provided 2020-11-27 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001153109 SCV001314364 uncertain significance Usher syndrome, type 2C 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000585241 SCV001552655 uncertain significance not provided no assertion criteria provided clinical testing The ADGRV1 p.Asp3992Asn variant was identified in 2 of 896 proband chromosomes (frequency: 0.002) from individuals or families with Usher syndrome (Eandi_2017_PMID:29142287; Bonnet_2016_PMID:27460420). The variant was also identified in dbSNP (ID: rs201386977), ClinVar (classified as a VUS by GeneDx, EGL Genetics, Athena Diagnostics, ARUP and Praxis fuer Humangenetik Tuebingen and as likely benign by Laboratory for Molecular Medicine) and LOVD 3.0. The variant was not identified in Cosmic. The variant was identified in control databases in 320 of 228350 chromosomes at a frequency of 0.001401 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 54 of 9380 chromosomes (freq: 0.005757), Latino in 60 of 28672 chromosomes (freq: 0.002093), Other in 11 of 6242 chromosomes (freq: 0.001762), European (non-Finnish) in 168 of 99320 chromosomes (freq: 0.001692), South Asian in 19 of 25506 chromosomes (freq: 0.000745), European (Finnish) in 5 of 22700 chromosomes (freq: 0.00022) and African in 3 of 20596 chromosomes (freq: 0.000146), while the variant was not observed in the East Asian population. The p.Asp3992 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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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