VCV000256277.39 - ClinVar

NM_033380.3(COL4A5):c.1289C>A (p.Ala430Asp)

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.

(11)

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.1289C>A (p.Ala430Asp)

Variation ID: 256277 Accession: VCV000256277.39

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq22.3 X: 108591181 (GRCh38) [ NCBI UCSC ] X: 107834411 (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	Oct 3, 2016	Oct 20, 2024	Apr 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_033380.3:c.1289C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_203699.1:p.Ala430Asp	missense
NM_000495.5:c.1289C>A	NP_000486.1:p.Ala430Asp	missense
NC_000023.11:g.108591181C>A
NC_000023.10:g.107834411C>A
NG_011977.2:g.156258C>A
LRG_232:g.156258C>A
LRG_232t1:c.1289C>A	LRG_232p1:p.Ala430Asp
LRG_232t2:c.1289C>A	LRG_232p2:p.Ala430Asp
	P29400:p.Ala430Asp

... more HGVS ... less HGVS

Protein change

A430D

Other names

Canonical SPDI

NC_000023.11:108591180:C:A

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.

0.00238 (A)

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

The Genome Aggregation Database (gnomAD) 0.00418

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00454

1000 Genomes Project 30x 0.00187

1000 Genomes Project 0.00238

Trans-Omics for Precision Medicine (TOPMed) 0.00366

Links

ClinGen: CA10488704 UniProtKB: P29400#VAR_001933 dbSNP: rs142883891 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	2613	2795

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.
not specified	Benign/Likely benign (3)	criteria provided, multiple submitters, no conflicts	Feb 18, 2022	RCV000249325.18
not provided	Benign/Likely benign (6)	criteria provided, multiple submitters, no conflicts	Apr 1, 2024	RCV000422908.37
X-linked Alport syndrome	Likely benign (2)	criteria provided, single submitter	Apr 8, 2022	RCV001828136.10

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 (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000304527.1 First in ClinVar: Oct 03, 2016 Last updated: Oct 03, 2016
Benign (Jun 07, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000511374.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017
Likely benign (Mar 21, 2016)	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: SCV000966418.1 First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019	Comment: p.Ala430Asp in exon 20 of COL4A5: This variant is not expected to have clinical significance because it has been identified in 1.17% (53/4522) of Finnish … (more) p.Ala430Asp in exon 20 of COL4A5: This variant is not expected to have clinical significance because it has been identified in 1.17% (53/4522) of Finnish chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs142883891). (less) Number of individuals with the variant: 1
Benign (Jul 09, 2019)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV001143244.1 First in ClinVar: Jan 19, 2020 Last updated: Jan 19, 2020	Publications: PubMed (2) PubMed: 9195222‚ 31144478
Benign (Jan 31, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001759742.1 First in ClinVar: Jul 24, 2021 Last updated: Jul 24, 2021	Comment: This variant is associated with the following publications: (PMID: 31144478, 8940267)
Benign (Feb 18, 2022)	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: SCV002103518.1 First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022	Comment: Variant summary: COL4A5 c.1289C>A (p.Ala430Asp) results in a non-conservative amino acid change located in the Collagen triple helix repeat (IPR008160) of the encoded protein sequence. … (more) Variant summary: COL4A5 c.1289C>A (p.Ala430Asp) results in a non-conservative amino acid change located in the Collagen triple helix repeat (IPR008160) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0047 in 182887 control chromosomes, including 342 hemizygotes and 1 homozygote in the general population (gnomAD). The variant was predominantly at a frequency of 0.0056 within the Non-Finnish European subpopulation in the gnomAD database, including 175 hemizygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.21 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL4A5 causing Alport Syndrome 1, X-Linked Recessive phenotype (0.0046), strongly suggesting that the variant is a benign polymorphism. Six ClinVar submitters have assessed the variant since 2014: five have classified the variant as benign and one as likely benign. Based on the evidence outlined above, the variant was classified as benign. (less)
Benign (Jan 31, 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: SCV001091795.6 First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024
Likely benign (Apr 08, 2022)	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: SCV002808886.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
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: SCV005206694.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (Apr 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV002546189.16 First in ClinVar: Jul 09, 2022 Last updated: Oct 20, 2024	Comment: COL4A5: BS1, BS2 Number of individuals with the variant: 7
Benign (Dec 03, 2019)	no assertion criteria provided Method: clinical testing	X-linked Alport syndrome Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002081380.1 First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022
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Comment:

p.Ala430Asp in exon 20 of COL4A5: This variant is not expected to have clinical significance because it has been identified in 1.17% (53/4522) of Finnish chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs142883891).

Comment:

Variant summary: COL4A5 c.1289C>A (p.Ala430Asp) results in a non-conservative amino acid change located in the Collagen triple helix repeat (IPR008160) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0047 in 182887 control chromosomes, including 342 hemizygotes and 1 homozygote in the general population (gnomAD). The variant was predominantly at a frequency of 0.0056 within the Non-Finnish European subpopulation in the gnomAD database, including 175 hemizygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.21 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL4A5 causing Alport Syndrome 1, X-Linked Recessive phenotype (0.0046), strongly suggesting that the variant is a benign polymorphism. Six ClinVar submitters have assessed the variant since 2014: five have classified the variant as benign and one as likely benign. Based on the evidence outlined above, the variant was classified as benign.

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
Genotype-phenotype correlation and prognostic impact in Chinese patients with Alport Syndrome.	Shang S	Molecular genetics & genomic medicine	2019	PMID: 31144478
The clinical spectrum of type IV collagen mutations.	Lemmink HH	Human mutation	1997	PMID: 9195222

Text-mined citations for rs142883891 ...

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 Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_033380.3(COL4A5):c.1289C>A (p.Ala430Asp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs142883891 ...