NM_033380.3(COL4A5):c.4964T>G (p.Leu1655Arg) AND Alport syndrome 1, X-linked recessive

Clinical significance:Pathogenic (Last evaluated: Dec 16, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000011212.13

Allele description [Variation Report for NM_033380.3(COL4A5):c.4964T>G (p.Leu1655Arg)]

NM_033380.3(COL4A5):c.4964T>G (p.Leu1655Arg)

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.4964T>G (p.Leu1655Arg)
HGVS:
  • NC_000023.11:g.108695409T>G
  • NG_011977.1:g.260486T>G
  • NG_011977.2:g.260486T>G
  • NM_000495.5:c.4946T>G
  • NM_033380.3:c.4964T>GMANE SELECT
  • NP_000486.1:p.Leu1649Arg
  • NP_203699.1:p.Leu1655Arg
  • LRG_232t1:c.4946T>G
  • LRG_232t2:c.4964T>G
  • LRG_232:g.260486T>G
  • LRG_232p1:p.Leu1649Arg
  • LRG_232p2:p.Leu1655Arg
  • NC_000023.10:g.107938639T>G
  • NM_000495.3:c.4946T>G
  • NM_000495.4:c.4946T>G
  • NM_033380.1:c.4964T>G
  • NM_033380.2:c.4964T>G
  • NP_203699.1:p.Leu1649Arg
  • P29400:p.Leu1649Arg
  • p.LEU1655ARG
Protein change:
L1649R; LEU1649ARG
Links:
UniProtKB: P29400#VAR_001973; OMIM: 303630.0014; dbSNP: rs104886303
NCBI 1000 Genomes Browser:
rs104886303
Molecular consequence:
  • NM_000495.5:c.4946T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033380.3:c.4964T>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Alport syndrome 1, X-linked recessive (ATS1)
Synonyms:
NEPHROPATHY AND DEAFNESS, X-LINKED; Alport Syndrome and Thin Basement Membrane Nephropathy; X-linked Alport syndrome; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0010520; MedGen: C4746986; Orphanet: 63; Orphanet: 88917; OMIM: 301050

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000031439OMIMno assertion criteria providedPathogenic
(Jun 1, 1996)
germlineliterature only

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

SCV000057825GeneReviewsno assertion criteria providedpathologic
(Feb 28, 2013)
not providedcuration

SCV000893815Fulgent Genetics,Fulgent Geneticscriteria provided, single submitter
Pathogenic
(Oct 31, 2018)
unknownclinical testing

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

SCV001156656ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratoriescriteria provided, single submitter
Pathogenic
(Dec 16, 2019)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providednot providednot providednot providednot providednot providednot providednot providedcuration
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

A mutation causing Alport syndrome with tardive hearing loss is common in the western United States.

Barker DF, Pruchno CJ, Jiang X, Atkin CL, Stone EM, Denison JC, Fain PR, Gregory MC.

Am J Hum Genet. 1996 Jun;58(6):1157-65.

PubMed [citation]
PMID:
8651292
PMCID:
PMC1915056

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

Details of each submission

From OMIM, SCV000031439.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

Barker et al. (1996) identified a novel leu1649-to-arg (L1649R) mutation in the COL4A5 gene in Alport syndrome (ALS1; 301050) patients. In contrast to most described COL4A5 mutations in Alport syndrome, each of which accounts for the disease in a single family, the L1649R mutation was found in over 7% of the 121 families studied. In males with the L1649R mutation, renal failure preceded hearing loss by approximately 10 years, and the cumulative frequency of hearing loss is 60% by age 60. Barker et al. (1996) noted that substantial variability occurs in the ages at appearance of end-stage renal disease and functional hearing loss among individuals with identical mutations, emphasizing the fallibility of generalizations about the phenotype associated with a specific mutation that is observed in only a small number of Alport syndrome patients.

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

From GeneReviews, SCV000057825.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

Converted during submission to Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1not providednot providednot providednot providedAssert pathogenicitynot providednot providednot providednot provided

From Fulgent Genetics,Fulgent Genetics, SCV000893815.1

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

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001156656.2

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

Description

The COL4A5 c.4946T>G; p.Leu1649Arg variant (rs104886303), also reported as Leu1655Arg, has been described in multiple individuals and families affected with Alport syndrome and is associated with a mild phenotype presenting in adulthood (Barker 1996, Barker 2001, Kobayashi 2008, Martin 1998, Pont-Kingdon 2009). It is reported as pathogenic by multiple sources in ClinVar (Variation ID: 10466), and is absent from general population databases (Exome Variant Server and Genome Aggregation Database), indicating it is not a common polymorphism. The leucine at codon 1649 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. In agreement with this, in vitro analysis of the variant protein demonstrates defective trimerization, leading to secretion of a less stable monomeric alpha chain (Kobayashi 2008). Based on available information, this variant is considered pathogenic. REFERENCES Barker D et al. A mutation causing Alport syndrome with tardive hearing loss is common in the western United States. Am J Hum Genet. 1996 Jun;58(6):1157-65. Barker D et al. Efficient detection of Alport syndrome COL4A5 mutations with multiplex genomic PCR-SSCP. Am J Med Genet. 2001 Jan 15;98(2):148-60. Kobayashi T et al. Mutational analysis of type IV collagen alpha5 chain, with respect to heterotrimer formation. Biochem Biophys Res Commun. 2008 Feb 1;366(1):60-5. Martin P et al. High mutation detection rate in the COL4A5 collagen gene in suspected Alport syndrome using PCR and direct DNA sequencing. J Am Soc Nephrol. 1998 Dec;9(12):2291-301. Pont-Kingdon G et al. Molecular testing for adult type Alport syndrome. BMC Nephrol. 2009 Nov 17;10:38.

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

Last Updated: Nov 20, 2021

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