VCV000024554.32 - ClinVar

NM_033380.3(COL4A5):c.2692A>G (p.Met898Val)

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.

Conflicting classifications of pathogenicity
Pathogenic(1); Benign(3); Likely benign(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_033380.3(COL4A5):c.2692A>G (p.Met898Val)

Variation ID: 24554 Accession: VCV000024554.32

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq22.3 X: 108621817 (GRCh38) [ NCBI UCSC ] X: 107865047 (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	Oct 26, 2024	Aug 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_033380.3:c.2692A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_203699.1:p.Met898Val	missense
NM_000495.5:c.2692A>G	NP_000486.1:p.Met898Val	missense
NC_000023.11:g.108621817A>G
NC_000023.10:g.107865047A>G
NG_011977.2:g.186894A>G
LRG_232:g.186894A>G
LRG_232t1:c.2692A>G	LRG_232p1:p.Met898Val
LRG_232t2:c.2692A>G	LRG_232p2:p.Met898Val
	P29400:p.Met898Val

... more HGVS ... less HGVS

Protein change

M898V

Other names

Canonical SPDI

NC_000023.11:108621816:A: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.

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

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00009

Trans-Omics for Precision Medicine (TOPMed) 0.00015

The Genome Aggregation Database (gnomAD) 0.00017

Exome Aggregation Consortium (ExAC) 0.00030

The Genome Aggregation Database (gnomAD), exomes 0.00030

Links

ClinGen: CA258739 UniProtKB: P29400#VAR_011258 dbSNP: rs104886192 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	2625	2807

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	Conflicting interpretations of pathogenicity (5)	criteria provided, conflicting classifications	May 1, 2024	RCV000021433.14
not provided	Benign/Likely benign (3)	criteria provided, multiple submitters, no conflicts	Jan 28, 2024	RCV000885639.20
Autosomal dominant Alport syndrome	no classifications from unflagged records (1)	no classifications from unflagged records	Dec 13, 2023	RCV001849276.3
COL4A5-related disorder	Likely benign (1)	no assertion criteria provided	Jun 15, 2019	RCV003904858.2
not specified	Likely benign (1)	criteria provided, single submitter	Aug 1, 2024	RCV004767014.1

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.
Benign (Aug 30, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	X-linked Alport syndrome Affected status: unknown Allele origin: maternal	Centogene AG - the Rare Disease Company Accession: SCV002028342.1 First in ClinVar: Dec 04, 2021 Last updated: Dec 04, 2021
Benign (Jan 28, 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: SCV001029101.6 First in ClinVar: Dec 17, 2019 Last updated: Feb 14, 2024
Pathogenic (May 01, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	X-linked Alport syndrome Affected status: yes Allele origin: germline	Laboratory of Prof. Karen Avraham, Tel Aviv University Accession: SCV005073737.1 First in ClinVar: Jul 15, 2024 Last updated: Jul 15, 2024 Comment: XLD; high-tone HL, normal-profound	Comment: Pathogenic by Deafness Variation Database based on PMID:30773290 Number of individuals with the variant: 1 Ethnicity/Population group: Jewish Geographic origin: Israel Testing laboratory: Prof. Karen Avraham, Tel Aviv University, Israel Date variant was reported to submitter: 2024-05-02
Benign (Oct 21, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001863032.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021	Comment: This variant is associated with the following publications: (PMID: 30773290, 11223851, 25525159, 20378821)
Likely benign (Sep 01, 2023)	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: SCV004167398.10 First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024	Comment: COL4A5: BS2 Number of individuals with the variant: 1
Likely benign (Aug 01, 2024)	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: SCV005381640.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024	Publications: PubMed (3) PubMed: 30773290‚ 11223851‚ 33369211 Comment: Variant summary: COL4A5 c.2692A>G (p.Met898Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign … (more) Variant summary: COL4A5 c.2692A>G (p.Met898Val) results in a conservative amino acid change in 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 0.00022 in 1203910 control chromosomes, including 85 hemizygotes (gnomAD v4.1.0). c.2692A>G has been reported in the literature in individuals with clinical features of Alport syndrome (e.g., Barker_2001, Connaughton_2019, Uliana_2021), however these report(s) do not provide unequivocal conclusions about association of the variant with Alport Syndrome 1, X-Linked Recessive. Co-occurrences with other pathogenic variant(s) have been reported (INF2 c.353T>A, p.Ile118Asn), providing supporting evidence for a benign role (Connaughton_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 11223851, 30773290, 33369211). ClinVar contains an entry for this variant (Variation ID: 24554). Based on the evidence outlined above, the variant was classified as likely benign. (less)
Likely benign (Jun 15, 2019)	no assertion criteria provided Method: clinical testing	COL4A5-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004720696.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Likely benign (Jan 15, 2020)	no assertion criteria provided Method: clinical testing	X-linked Alport syndrome Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002083650.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022
Pathogenic (Mar 11, 2020)	Flagged submission flagged submission (ACMG Guidelines, 2015) Method: clinical testing Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	X-linked Alport syndrome Affected status: yes Allele origin: germline	Medical Genetics, University of Parma Accession: SCV001245123.1 First in ClinVar: May 04, 2020 Last updated: May 04, 2020
Pathogenic (Feb 14, 2019)	Flagged submission flagged submission Method: literature only Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	Autosomal dominant Alport syndrome Affected status: yes Allele origin: germline	Yale Center for Mendelian Genomics, Yale University Study: Yale Center for Mendelian Genomics Accession: SCV002106605.1 First in ClinVar: Mar 28, 2022 Last updated: Mar 28, 2022	Publications: PubMed (1) PubMed: 30773290
Uncertain significance (May 18, 2021)	Flagged submission flagged submission (ACMG Guidelines, 2015) Method: clinical testing Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	X-linked Alport syndrome Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV001737201.1 First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021	Sex: mixed
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more

Comment:

Variant summary: COL4A5 c.2692A>G (p.Met898Val) results in a conservative amino acid change in 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 0.00022 in 1203910 control chromosomes, including 85 hemizygotes (gnomAD v4.1.0). c.2692A>G has been reported in the literature in individuals with clinical features of Alport syndrome (e.g., Barker_2001, Connaughton_2019, Uliana_2021), however these report(s) do not provide unequivocal conclusions about association of the variant with Alport Syndrome 1, X-Linked Recessive. Co-occurrences with other pathogenic variant(s) have been reported (INF2 c.353T>A, p.Ile118Asn), providing supporting evidence for a benign role (Connaughton_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 11223851, 30773290, 33369211). ClinVar contains an entry for this variant (Variation ID: 24554). Based on the evidence outlined above, the variant was classified as likely 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
Deciphering the pathogenesis of the COL4-related hematuric nephritis: A genotype/phenotype study.	Uliana V	Molecular genetics & genomic medicine	2021	PMID: 33369211
Monogenic causes of chronic kidney disease in adults.	Connaughton DM	Kidney international	2019	PMID: 30773290
Efficient detection of Alport syndrome COL4A5 mutations with multiplex genomic PCR-SSCP.	Barker DF	American journal of medical genetics	2001	PMID: 11223851

Text-mined citations for rs104886192 ...

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 Oct 27, 2024

ClinVar Genomic variation as it relates to human health

NM_033380.3(COL4A5):c.2692A>G (p.Met898Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs104886192 ...