NM_033380.3(COL4A5):c.4937A>G (p.Tyr1646Cys) AND X-linked Alport syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 29, 2021
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001802465.8

Allele description [Variation Report for NM_033380.3(COL4A5):c.4937A>G (p.Tyr1646Cys)]

NM_033380.3(COL4A5):c.4937A>G (p.Tyr1646Cys)

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.4937A>G (p.Tyr1646Cys)

HGVS:

NC_000023.11:g.108695382A>G
NG_011977.2:g.260459A>G
NM_000495.5:c.4919A>G
NM_033380.3:c.4937A>GMANE SELECT
NP_000486.1:p.Tyr1640Cys
NP_203699.1:p.Tyr1646Cys
LRG_232t1:c.4919A>G
LRG_232t2:c.4937A>G
LRG_232:g.260459A>G
LRG_232p1:p.Tyr1640Cys
LRG_232p2:p.Tyr1646Cys
NC_000023.10:g.107938612A>G
NM_000495.3:c.4919A>G

Protein change:

Y1640C

Links:

dbSNP: rs937985430

NCBI 1000 Genomes Browser:

rs937985430

Molecular consequence:

NM_000495.5:c.4919A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_033380.3:c.4937A>G - 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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002048570	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Uncertain significance (Sep 26, 2021)	germline	clinical testing	Citation Link,
SCV002794144	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 29, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002048570

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2021)

Uncertain significance
(Sep 26, 2021)

germline

clinical testing

Citation Link,

SCV002794144

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 29, 2021)

unknown

clinical testing

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

Help

Summary from all submissions

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

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

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV002048570.1

#	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.4919A>G; p.Tyr1640Cys (rs937985430), to our knowledge, is not reported in the medical literature or gene specific databases. This variant is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The tyrosine at codon 1640 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.938). Additionally, this variant creates a cysteine residue in the non-collagenous (NC) domain, which is critical for collagen chain assembly and considered a well-established functional domain (Savige 2021, Sundaramoorthy 2002). The NC domain contains 12 highly conserved cysteine residues and the disulfide bridges formed between these residues are essential for protein folding and stability; loss of one of these cysteines may interfere with proper disulfide bridge formation, disrupting protein structure. While it is possible that creation of a cysteine residue would impact protein structure, there is insufficient evidence at this time. Therefore, due to limited information, the clinical significance of the p.Tyr1640Cys variant is uncertain at this time. References: Savige J et al. Consensus statement on standards and guidelines for the molecular diagnostics of Alport syndrome: refining the ACMG criteria. Eur J Hum Genet. 2021 Aug;29(8):1186-1197. PMID: 33854215. Sundaramoorthy M et al. Crystal structure of NC1 domains. Structural basis for type IV collagen assembly in basement membranes. J Biol Chem. 2002 Aug 23;277(34):31142-53. PMID: 11970952.

#	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

From Fulgent Genetics, Fulgent Genetics, SCV002794144.1

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

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

Last Updated: May 1, 2024

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