VCV000024398.32 - ClinVar

NM_033380.3(COL4A5):c.1331T>G (p.Ile444Ser)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(13)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Benign/Likely benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_033380.3(COL4A5):c.1331T>G (p.Ile444Ser)

Variation ID: 24398 Accession: VCV000024398.32

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq22.3 X: 108591223 (GRCh38) [ NCBI UCSC ] X: 107834453 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Sep 29, 2024	Feb 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_033380.3:c.1331T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_203699.1:p.Ile444Ser	missense
NM_000495.5:c.1331T>G	NP_000486.1:p.Ile444Ser	missense
NM_033380.1:c.1331T>G
NC_000023.11:g.108591223T>G
NC_000023.10:g.107834453T>G
NG_011977.2:g.156300T>G
LRG_232:g.156300T>G
LRG_232t1:c.1331T>G	LRG_232p1:p.Ile444Ser
LRG_232t2:c.1331T>G	LRG_232p2:p.Ile444Ser
	P29400:p.Ile444Ser

... more HGVS ... less HGVS

Protein change

I444S

Other names

Canonical SPDI

NC_000023.11:108591222:T:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.14940 (G)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.11020

Trans-Omics for Precision Medicine (TOPMed) 0.12048

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.12157

1000 Genomes Project 0.14940

1000 Genomes Project 30x 0.15858

The Genome Aggregation Database (gnomAD), exomes 0.04469

Exome Aggregation Consortium (ExAC) 0.05118

Links

ClinGen: CA258459 UniProtKB: P29400#VAR_001934 dbSNP: rs2272946 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
COL4A5		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	2615	2797

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
X-linked Alport syndrome	Benign (3)	criteria provided, multiple submitters, no conflicts	Nov 3, 2023	RCV000021277.14
not specified	Benign/Likely benign (6)	criteria provided, multiple submitters, no conflicts	Dec 10, 2021	RCV000254318.17
not provided	Benign/Likely benign (3)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV001519072.7
Focal segmental glomerulosclerosis	Benign (1)	criteria provided, single submitter	Aug 16, 2022	RCV002293987.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely benign (Dec 10, 2021)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002050899.1 First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022
Benign (Aug 16, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Inherited focal segmental glomerulosclerosis Affected status: unknown Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002587279.1 First in ClinVar: Oct 29, 2022 Last updated: Oct 29, 2022
Benign (Oct 21, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	X-linked Alport syndrome Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002806080.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Benign (Mar 03, 2015)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001946080.2 First in ClinVar: Sep 29, 2021 Last updated: Mar 04, 2023	Comment: This variant is associated with the following publications: (PMID: 8648925, 27884173, 11223851, 10561141, 8940267, 30245029)
Benign (Nov 03, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	X-linked Alport syndrome Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000883651.3 First in ClinVar: Feb 18, 2019 Last updated: Feb 20, 2024
Benign (Feb 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001727877.4 First in ClinVar: Jun 15, 2021 Last updated: Feb 28, 2024
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000304528.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Benign (Apr 07, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000340577.4 First in ClinVar: Dec 06, 2016 Last updated: Apr 09, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=COL4A5 Number of individuals with the variant: 2 Sex: mixed
Benign (Nov 22, 2017)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000713737.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018	Publications: PubMed (6) PubMed: 10561141‚ 14993485‚ 8648925‚ 15780079‚ 21505094‚ 27281700 Comment: p.Ile444Ser in exon 20 of COL4A5: This variant is not expected to have clinical significance because it has been identified in 34% (6123/17969) of African … (more) p.Ile444Ser in exon 20 of COL4A5: This variant is not expected to have clinical significance because it has been identified in 34% (6123/17969) of African chrom osomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute. org; dbSNP rs2272946). ACMG/AMP Criteria applied: BA1. (less) Number of individuals with the variant: 20
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (X-linked inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005206695.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001959291.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Benign (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	X-linked Alport syndrome Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001458770.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001931867.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
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Comment:

p.Ile444Ser in exon 20 of COL4A5: This variant is not expected to have clinical significance because it has been identified in 34% (6123/17969) of African chrom osomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute. org; dbSNP rs2272946). ACMG/AMP Criteria applied: BA1.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Genetic, Clinical, and Pathologic Backgrounds of Patients with Autosomal Dominant Alport Syndrome.	Kamiyoshi N	Clinical journal of the American Society of Nephrology : CJASN	2016	PMID: 27281700
Twenty-one novel mutations identified in the COL4A5 gene in Chinese patients with X-linked Alport's syndrome confirmed by skin biopsy.	Ma J	Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association	2011	PMID: 21505094
Detection of mutations in the COL4A5 gene by analyzing cDNA of skin fibroblasts.	Wang F	Kidney international	2005	PMID: 15780079
Detection of COL4A5 gene mutations in Chinese patients with Alport's syndrome.	Pan X	Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association	2004	PMID: 14993485
Detection of mutations in the COL4A5 gene in over 90% of male patients with X-linked Alport's syndrome by RT-PCR and direct sequencing.	Inoue Y	American journal of kidney diseases : the official journal of the National Kidney Foundation	1999	PMID: 10561141
The COL4A5 gene in Japanese Alport syndrome patients: spectrum of mutations of all exons. The Japanese Alport Network.	Kawai S	Kidney international	1996	PMID: 8648925
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=COL4A5	-	-	-	-

Text-mined citations for rs2272946 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_033380.3(COL4A5):c.1331T>G (p.Ile444Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs2272946 ...