NM_033380.3(COL4A5):c.4709G>C (p.Cys1570Ser) AND X-linked Alport syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 6, 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:: RCV000021640.14

Allele description [Variation Report for NM_033380.3(COL4A5):c.4709G>C (p.Cys1570Ser)]

NM_033380.3(COL4A5):c.4709G>C (p.Cys1570Ser)

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.4709G>C (p.Cys1570Ser)

Other names:

C108S

HGVS:

NC_000023.11:g.108694809G>C
NG_011977.2:g.259886G>C
NM_000495.5:c.4691G>C
NM_033380.3:c.4709G>CMANE SELECT
NP_000486.1:p.Cys1564Ser
NP_203699.1:p.Cys1570Ser
LRG_232t1:c.4691G>C
LRG_232t2:c.4709G>C
LRG_232:g.259886G>C
LRG_232p1:p.Cys1564Ser
LRG_232p2:p.Cys1570Ser
NC_000023.10:g.107938039G>C
NM_000495.4:c.4691G>C
P29400:p.Cys1564Ser
NM_000495.3:c.4692G>C

Note:

NCBI staff reviewed the sequence information reported in PubMed 1672282 to determine the location of this allele on current reference sequence.

Protein change:

C1564S; CYS108SER

Links:

LOVD 3: COL4A5_000203; UniProtKB: P29400#VAR_001971; OMIM: 303630.0002; dbSNP: rs104886287

NCBI 1000 Genomes Browser:

rs104886287

Molecular consequence:

NM_000495.5:c.4691G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_033380.3:c.4709G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

Recent activity

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put. cytoplasmic tyrosine kinase [Homo sapiens]
put. cytoplasmic tyrosine kinase [Homo sapiens]
gi|30315|emb|CAA42713.1|

Protein
DC116804 Yamamoto/Hyodo-Miura NIBB/NBRP Xenopus DMZ pCS2p+ cDNA library Xenopus ...
DC116804 Yamamoto/Hyodo-Miura NIBB/NBRP Xenopus DMZ pCS2p+ cDNA library Xenopus laevis cDNA clone xl277f17 5', mRNA sequence
gi|119095367|gnl|dbEST|43365387|dbj 6804.1|

Nucleotide
DC135138 Yamamoto/Hyodo-Miura NIBB/NBRP Xenopus DMZ pCS2p+ cDNA library Xenopus ...
DC135138 Yamamoto/Hyodo-Miura NIBB/NBRP Xenopus DMZ pCS2p+ cDNA library Xenopus laevis cDNA clone xl340m19 5', mRNA sequence
gi|119129101|gnl|dbEST|43394055|dbj 5138.1|

Nucleotide
NISC_nl19e01.x1 NICHD_XGC_Emb7 Xenopus tropicalis cDNA clone IMAGE:5379168 3', m...
NISC_nl19e01.x1 NICHD_XGC_Emb7 Xenopus tropicalis cDNA clone IMAGE:5379168 3', mRNA sequence
gi|21381817|gnl|dbEST|12634243|gb|B 48.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000031427	OMIM	no assertion criteria provided	Pathogenic (Dec 1, 1991)	germline	literature only	PubMed (6) [See all records that cite these PMIDs] 14856448, 13582260, 6650503, 2349482, 1672282, 1783380
SCV000057824	GeneReviews	no assertion criteria provided	pathologic (Feb 28, 2013)	not provided	curation
SCV001158664	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Pathogenic (Jan 6, 2021)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000031427

OMIM

no assertion criteria provided

Pathogenic
(Dec 1, 1991)

germline

literature only

PubMed (6)
[See all records that cite these PMIDs]

SCV000057824

GeneReviews

no assertion criteria provided

pathologic
(Feb 28, 2013)

not provided

curation

SCV001158664

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2021)

Pathogenic
(Jan 6, 2021)

germline

clinical testing

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

A clinical study of hereditary interstitial pyelonephritis.

PERKOFF GT, STEPHENS FE, DOLOWITZ DA, TYLER FH.

AMA Arch Intern Med. 1951 Aug;88(2):191-200. No abstract available.

PubMed [citation]

PMID:: 14856448

A follow-up study of hereditary chronic nephritis.

PERKOFF GT, NUGENT CA Jr, DOLOWITZ DA, STEPHENS FE, CARNES WH, TYLER FH.

AMA Arch Intern Med. 1958 Nov;102(5):733-46. No abstract available.

PubMed [citation]

PMID:: 13582260

See all PubMed Citations (6)

Details of each submission

From OMIM, SCV000031427.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (6)

Description

In the historic kindred P in Utah studied by Perkoff et al. (1951, 1958) and later by Hasstedt and Atkin (1983), Barker et al. (1990) demonstrated that a PstI site variant segregated in complete linkage with the presence or absence of the Alport phenotype (ALS1; 301050). All 23 gene-carrying mothers were heterozygous; a total of 45 sons showed complete linkage. In an addendum, Barker et al. (1990) stated that by PCR amplification and DNA sequencing, the PstI variant had been shown to be due to a single basepair change that converted a highly conserved cysteine codon in the noncollagenase (NC) domain to a codon for serine (C108S). (The NC domain of glomerular basement membrane type IV collagen has been shown to be absent or altered in Alport syndrome on the basis of studies with antibodies directed against this portion of the molecule.) Zhou et al. (1991) described the generation of a new BglII site and showed that the cys-to-ser change occurred in the third to the last exon. Boye et al. (1991) commented that the defect had been defined as a G-to-C transition in exon 3 that created both a PstI and a BglII site.

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

From GeneReviews, SCV000057824.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

Converted during submission to Pathogenic.

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

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001158664.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The COL4A5 c.4691G>C; p.Cys1564Ser variant (rs104886287) is reported in the medical literature segregating with Alport syndrome in a large kindred (Pont-Kingdon 2009, Zhou 1991). It is reported as pathogenic in ClinVar (Variation ID: 24761) and is absent from general population databases (Exome Variant Server and Genome Aggregation Database), indicating it is not a common polymorphism. The cysteine at codon 1564 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.96). Additionally, this is one of twelve cysteine residues located in the carboxy-terminal domain important for formation of triple helices or networks involving collagen alpha5(IV) chains (Kashtan 2001). Based on available information, this variant is considered pathogenic. References: Kashtan CE. Alport Syndrome and Thin Basement Membrane Nephropathy. 2001 Aug 28 (Updated 2015 Nov 25). In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 1993-2017. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1207/ Pont-Kingdon G et al. Molecular testing for adult type Alport syndrome. BMC Nephrol. 2009 Nov 17;10:38. doi: 10.1186/1471-2369-10-38. Zhou J et al. Single base mutation in alpha 5(IV) collagen chain gene converting a conserved cysteine to serine in Alport syndrome. Genomics. 1991 Jan;9(1):10-8.

#	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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