NM_032119.4(ADGRV1):c.14365C>T (p.Arg4789Trp) AND not provided

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Pathogenic(1);Uncertain significance(1) (Last evaluated: Mar 20, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000493267.3

Allele description [Variation Report for NM_032119.4(ADGRV1):c.14365C>T (p.Arg4789Trp)]

NM_032119.4(ADGRV1):c.14365C>T (p.Arg4789Trp)

Gene:
ADGRV1:adhesion G protein-coupled receptor V1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
5q14.3
Genomic location:
Preferred name:
NM_032119.4(ADGRV1):c.14365C>T (p.Arg4789Trp)
HGVS:
  • NC_000005.10:g.90791194C>T
  • NG_007083.2:g.266851C>T
  • NM_032119.4:c.14365C>TMANE SELECT
  • NP_115495.3:p.Arg4789Trp
  • LRG_1095t1:c.14365C>T
  • LRG_1095:g.266851C>T
  • LRG_1095p1:p.Arg4789Trp
  • NC_000005.9:g.90087011C>T
  • NM_032119.3:c.14365C>T
  • NR_003149.2:n.14381C>T
Protein change:
R4789W
Links:
dbSNP: rs1131691924
NCBI 1000 Genomes Browser:
rs1131691924
Molecular consequence:
  • NM_032119.4:c.14365C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NR_003149.2:n.14381C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000583154GeneDxcriteria provided, single submitter
Likely pathogenic
(Aug 18, 2015)
germlineclinical testing

Citation Link,

SCV001142922Athena Diagnostics Inccriteria provided, single submitter
Uncertain significance
(Jul 2, 2019)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV001580151Invitaecriteria provided, single submitter
Pathogenic
(Mar 20, 2020)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, Bright AR, Previte D, Zhang K, Rowland CM, McCarthy M, Lapierre JL, Dubois F, Medeiros KA, Batish SD, Jones J, Liaquat K, Hoffman CA, Jaremko M, Wang Z, Sun W, Buller-Burckle A, et al.

Hum Mutat. 2016 Jan;37(1):127-34. doi: 10.1002/humu.22918. Epub 2015 Oct 29.

PubMed [citation]
PMID:
26467025
PMCID:
PMC4737317

Non-USH2A mutations in USH2 patients.

Besnard T, Vaché C, Baux D, Larrieu L, Abadie C, Blanchet C, Odent S, Blanchet P, Calvas P, Hamel C, Dollfus H, Lina-Granade G, Lespinasse J, David A, Isidor B, Morin G, Malcolm S, Tuffery-Giraud S, Claustres M, Roux AF.

Hum Mutat. 2012 Mar;33(3):504-10. doi: 10.1002/humu.22004. Epub 2012 Jan 6.

PubMed [citation]
PMID:
22147658
See all PubMed Citations (5)

Details of each submission

From GeneDx, SCV000583154.4

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

Description

The R4789W variant has been reported previously as a likely pathogenic variant in a cohort of patients diagnosed with Usher syndrome type 2 (Besnard et al. 2012). The R4789W variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R4789W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in this residue and in a nearby residue (R4789Q, N4885S) have been reported in the Human Gene Mutation Database in association with Usher syndrome (Stenson et al., 2014). Therefore, based on the currently available information, R4789W is a candidate for a disease-causing variant, although the possibility that it is a benign polymorphism cannot be completely excluded.

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

From Athena Diagnostics Inc, SCV001142922.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001580151.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces arginine with tryptophan at codon 4789 of the ADGRV1 protein (p.Arg4789Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Usher syndrome (PMID: 22147658, 26969326, Invitae). ClinVar contains an entry for this variant (Variation ID: 430362). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). This variant disrupts the p.Arg4789 amino acid residue in ADGRV1. Other variant(s) that disrupt this residue have been observed in individuals with ADGRV1-related conditions (PMID: 23462753), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Nov 27, 2021

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