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NM_033380.3(COL4A5):c.646G>A (p.Gly216Arg) AND not provided

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Dec 23, 2021
Review status:
criteria provided, conflicting classifications
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000681913.12

Allele description [Variation Report for NM_033380.3(COL4A5):c.646G>A (p.Gly216Arg)]

NM_033380.3(COL4A5):c.646G>A (p.Gly216Arg)

Gene:
COL4A5:collagen type IV alpha 5 chain [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Xq22.3
Genomic location:
Preferred name:
NM_033380.3(COL4A5):c.646G>A (p.Gly216Arg)
HGVS:
  • NC_000023.11:g.108578078G>A
  • NG_011977.2:g.143155G>A
  • NM_000495.5:c.646G>A
  • NM_033380.3:c.646G>AMANE SELECT
  • NP_000486.1:p.Gly216Arg
  • NP_203699.1:p.Gly216Arg
  • LRG_232t1:c.646G>A
  • LRG_232t2:c.646G>A
  • LRG_232:g.143155G>A
  • LRG_232p1:p.Gly216Arg
  • LRG_232p2:p.Gly216Arg
  • NC_000023.10:g.107821308G>A
  • NG_011977.1:g.143155G>A
  • P29400:p.Gly216Arg
Protein change:
G216R
Links:
UniProtKB: P29400#VAR_001919; dbSNP: rs104886067
NCBI 1000 Genomes Browser:
rs104886067
Molecular consequence:
  • NM_000495.5:c.646G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033380.3:c.646G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000809396Gharavi Laboratory, Columbia University
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Sep 16, 2018) 		germlineresearch

PubMed (1)
[See all records that cite this PMID]

SCV003445314Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Dec 23, 2021) 		germlineclinical testing

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

Help

Summary from all submissions

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Identification of 17 mutations in ten exons in the COL4A5 collagen gene, but no mutations found in four exons in COL4A6: a study of 250 patients with hematuria and suspected of having Alport syndrome.

Heiskari N, Zhang X, Zhou J, Leinonen A, Barker D, Gregory M, Atkin CL, Netzer KO, Weber M, Reeders S, Grönhagen-Riska C, Neumann HP, Trembath R, Tryggvason K.

J Am Soc Nephrol. 1996 May;7(5):702-9.

PubMed [citation]
PMID:
8738805
See all PubMed Citations (5)

Details of each submission

From Gharavi Laboratory, Columbia University, SCV000809396.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearch PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV003445314.2

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

Description

This missense change has been observed in individual(s) with Alport syndrome (PMID: 8738805). 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. This variant disrupts the p.Gly216 amino acid residue in COL4A5. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20378821, 22921432; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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: "Not Available"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 24307). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 216 of the COL4A5 protein (p.Gly216Arg).

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

Last Updated: Jun 17, 2024