NM_033380.3(COL4A5):c.4913G>A (p.Cys1638Tyr) AND not provided

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jun 14, 2021
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV002016059.7

Allele description [Variation Report for NM_033380.3(COL4A5):c.4913G>A (p.Cys1638Tyr)]

NM_033380.3(COL4A5):c.4913G>A (p.Cys1638Tyr)

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.4913G>A (p.Cys1638Tyr)

HGVS:

NC_000023.11:g.108695358G>A
NG_011977.2:g.260435G>A
NM_000495.5:c.4895G>A
NM_033380.3:c.4913G>AMANE SELECT
NP_000486.1:p.Cys1632Tyr
NP_203699.1:p.Cys1638Tyr
LRG_232t1:c.4895G>A
LRG_232t2:c.4913G>A
LRG_232:g.260435G>A
LRG_232p1:p.Cys1632Tyr
LRG_232p2:p.Cys1638Tyr
NC_000023.10:g.107938588G>A
NG_011977.1:g.260435G>A

Protein change:

C1632Y

Links:

dbSNP: rs1569509333

NCBI 1000 Genomes Browser:

rs1569509333

Molecular consequence:

NM_000495.5:c.4895G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_033380.3:c.4913G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002299391	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jun 14, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 20378821, 24033287, 26809805, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002299391

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jun 14, 2021)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Genotype-phenotype correlation in X-linked Alport syndrome.

Bekheirnia MR, Reed B, Gregory MC, McFann K, Shamshirsaz AA, Masoumi A, Schrier RW.

J Am Soc Nephrol. 2010 May;21(5):876-83. doi: 10.1681/ASN.2009070784. Epub 2010 Apr 8.

PubMed [citation]

PMID:: 20378821
PMCID:: PMC2865738

Unbiased next generation sequencing analysis confirms the existence of autosomal dominant Alport syndrome in a relevant fraction of cases.

Fallerini C, Dosa L, Tita R, Del Prete D, Feriozzi S, Gai G, Clementi M, La Manna A, Miglietti N, Mancini R, Mandrile G, Ghiggeri GM, Piaggio G, Brancati F, Diano L, Frate E, Pinciaroli AR, Giani M, Castorina P, Bresin E, Giachino D, De Marchi M, et al.

Clin Genet. 2014 Sep;86(3):252-7. doi: 10.1111/cge.12258. Epub 2013 Oct 17.

PubMed [citation]

PMID:: 24033287

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002299391.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This variant has been observed in individual(s) with X-linked Alport syndrome (PMID: 26809805). ClinVar contains an entry for this variant (Variation ID: 587218). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with tyrosine at codon 1632 of the COL4A5 protein (p.Cys1632Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt COL4A5 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Cys1632 ‚Äãamino acid residue in COL4A5. Other variant(s) that disrupt this residue have been observed in individuals with COL4A5-related conditions (PMID: 20378821, 24033287, 26809805), which suggests that this may be a clinically significant amino acid residue

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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