NM_033380.3(COL4A5):c.3659G>A (p.Gly1220Asp) AND X-linked Alport syndrome

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jul 15, 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:: RCV000021545.7

Allele description [Variation Report for NM_033380.3(COL4A5):c.3659G>A (p.Gly1220Asp)]

NM_033380.3(COL4A5):c.3659G>A (p.Gly1220Asp)

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.3659G>A (p.Gly1220Asp)

HGVS:

NC_000023.11:g.108668373G>A
NG_011977.2:g.233450G>A
NM_000495.5:c.3659G>A
NM_033380.3:c.3659G>AMANE SELECT
NP_000486.1:p.Gly1220Asp
NP_203699.1:p.Gly1220Asp
LRG_232t1:c.3659G>A
LRG_232t2:c.3659G>A
LRG_232:g.233450G>A
LRG_232p1:p.Gly1220Asp
LRG_232p2:p.Gly1220Asp
NC_000023.10:g.107911603G>A
NG_011977.1:g.233450G>A
NM_000495.3:c.3659G>A
NM_000495.4:c.3659G>A
P29400:p.Gly1220Asp

Protein change:

G1220D

Links:

UniProtKB: P29400#VAR_008011; dbSNP: rs104886251

NCBI 1000 Genomes Browser:

rs104886251

Molecular consequence:

NM_000495.5:c.3659G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_033380.3:c.3659G>A - 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
SCV001425052	Molecular Biology Laboratory, Fundació Puigvert - KidneyPanel_2020	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 1, 2020)	maternal	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 33532864
SCV001593041	Precision Medicine Center, Zhengzhou University	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	research	PubMed (1) [See all records that cite this PMID]
SCV001763592	INGEBI, INGEBI / CONICET	criteria provided, single submitter (ClinGen HL ACMG Specifications v1)	Pathogenic (Jul 15, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 10094548, 30311386

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001425052

Molecular Biology Laboratory, Fundació Puigvert - KidneyPanel_2020

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Feb 1, 2020)

maternal

research

PubMed (2)
[See all records that cite these PMIDs]

SCV001593041

Precision Medicine Center, Zhengzhou University

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

germline

research

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

SCV001763592

INGEBI, INGEBI / CONICET

criteria provided, single submitter

(ClinGen HL ACMG Specifications v1)

Pathogenic
(Jul 15, 2021)

germline

clinical testing

PubMed (2)
[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	maternal	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	research
Caucasian	germline	yes	not provided	not provided	not provided	not provided	no	clinical testing

Citations

PubMed

Clinical utility of genetic testing in early-onset kidney disease: seven genes are the main players.

Domingo-Gallego A, Pybus M, Bullich G, Furlano M, Ejarque-Vila L, Lorente-Grandoso L, Ruiz P, Fraga G, López González M, Piñero-Fernández JA, Rodríguez-Peña L, Llano-Rivas I, Sáez R, Bujons-Tur A, Ariceta G, Guirado L, Torra R, Ars E.

Nephrol Dial Transplant. 2022 Mar 25;37(4):687-696. doi: 10.1093/ndt/gfab019.

PubMed [citation]

PMID:: 33532864

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

See all PubMed Citations (4)

Details of each submission

From Molecular Biology Laboratory, Fundació Puigvert - KidneyPanel_2020, SCV001425052.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (2)

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

From Precision Medicine Center, Zhengzhou University, SCV001593041.1

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

Description

PM1:Located in a mutational hot spot PM2:not found in gnomAD PM5: Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before PP2:Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease PP3:Multiple lines of computational evidence support a deleterious effect on the gene or gene product

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

From INGEBI, INGEBI / CONICET, SCV001763592.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	not provided	not provided	no	clinical testing	PubMed (2)

Description

Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: The c.3659 G>A (p.Gly1220Asp) in COL4A5 gene is absent from population databases, so PM2 applied. This variant impacts a glycine residue in the Gly-X-Y motifs of the collagene gene which are criticial for triple helical structure formation meeting PM1 rule. Computational evidence predicted a damage impact of the mutation to the protein (PP3; REVEL:0.98). G1220D variant has been found twice in Alport Syndromes's patients (PMID: 10094548 and this report), applying to PP4 and PS4_Sup. Considering the infromation: PM2, PM1, PP3, PP4 and Ps4_Sup the variant is classified as Pathogenic.

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

Last Updated: Sep 29, 2024

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