NM_000092.4(COL4A4):c.1441G>A (p.Gly481Ser) AND not provided

Clinical significance:Conflicting interpretations of pathogenicity, Pathogenic(1);Uncertain significance(1) (Last evaluated: Oct 9, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000710831.3

Allele description [Variation Report for NM_000092.4(COL4A4):c.1441G>A (p.Gly481Ser)]

NM_000092.4(COL4A4):c.1441G>A (p.Gly481Ser)

Gene:
COL4A4:collagen type IV alpha 4 chain [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2q36.3
Genomic location:
Preferred name:
NM_000092.4(COL4A4):c.1441G>A (p.Gly481Ser)
HGVS:
  • NC_000002.12:g.227089886C>T
  • NG_011592.1:g.79674G>A
  • NM_000092.4:c.1441G>A
  • NP_000083.3:p.Gly481Ser
  • LRG_231t1:c.1441G>A
  • LRG_231:g.79674G>A
  • LRG_231p1:p.Gly481Ser
  • NC_000002.11:g.227954602C>T
Protein change:
G481S
Links:
dbSNP: rs181528936
NCBI 1000 Genomes Browser:
rs181528936
Molecular consequence:
  • NM_000092.4:c.1441G>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
SCV000841136Athena Diagnostics Inccriteria provided, single submitter
Pathogenic
(Jun 13, 2019)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV001555249Invitaecriteria provided, single submitter
Uncertain significance
(Oct 9, 2020)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot 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

Thin glomerular basement membrane disease: clinical significance of a morphological diagnosis--a collaborative study of the Italian Renal Immunopathology Group.

FrascĂ  GM, Onetti-Muda A, Mari F, Longo I, Scala E, Pescucci C, Roccatello D, Alpa M, Coppo R, Li Volti G, Feriozzi S, Bergesio F, Schena FP, Renieri A; Italian Renal Immunopathology Group..

Nephrol Dial Transplant. 2005 Mar;20(3):545-51. Epub 2004 Dec 23.

PubMed [citation]
PMID:
15618242
See all PubMed Citations (3)

Details of each submission

From Athena Diagnostics Inc, SCV000841136.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

The variant disrupts a glycine residue in the canonical Gly-X-Y repeats of the triple helix domain, which are required for stability and structure of this protein. Therefore it is expected to severely affect the function of the protein. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity.

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

From Invitae, SCV001555249.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces glycine with serine at codon 481 of the COL4A4 protein (p.Gly481Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs181528936, ExAC 0.08%). This variant has been observed in individual(s) with hematuria (PMID: 15618242). ClinVar contains an entry for this variant (Variation ID: 585525). 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). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Apr 18, 2021

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