VCV000553809.10 - ClinVar

NM_000092.5(COL4A4):c.5048G>A (p.Cys1683Tyr)

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.

(5)

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
Likely pathogenic(3); Uncertain significance(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000092.5(COL4A4):c.5048G>A (p.Cys1683Tyr)

Variation ID: 553809 Accession: VCV000553809.10

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q36.3 2: 227007350 (GRCh38) [ NCBI UCSC ] 2: 227872066 (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	Aug 5, 2018	Nov 17, 2024	Aug 29, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000092.5:c.5048G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000083.3:p.Cys1683Tyr	missense
NC_000002.12:g.227007350C>T
NC_000002.11:g.227872066C>T
NG_011592.1:g.162210G>A
LRG_231:g.162210G>A
LRG_231t1:c.5048G>A	LRG_231p1:p.Cys1683Tyr

... more HGVS ... less HGVS

Protein change

C1683Y

Other names

Canonical SPDI

NC_000002.12:227007349:C:T

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.

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

dbSNP: rs1386495377 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.
COL4A4		-	-	GRCh38 GRCh37	3010	3046

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.
Autosomal recessive Alport syndrome	Uncertain significance (1)	criteria provided, single submitter	Sep 8, 2017	RCV000669331.1
Hematuria, benign familial, 1	Uncertain significance (1)	criteria provided, single submitter	Apr 21, 2023	RCV004783836.1
not provided	Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Dec 11, 2023	RCV001861775.8
Autosomal dominant Alport syndrome	Likely pathogenic (1)	criteria provided, single submitter	Aug 29, 2024	RCV004760690.1

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.
Uncertain significance (Sep 08, 2017)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Autosomal recessive Alport syndrome Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000794075.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018	Publications: PubMed (1) PubMed: 26809805
Likely pathogenic (Dec 02, 2022)	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: SCV002288671.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 26809805 Comment: This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, … (more) This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1683 of the COL4A4 protein (p.Cys1683Tyr). This missense change has been observed in individuals with clinical features of autosomal dominant Alport syndrome (PMID: 26809805; Invitae). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COL4A4 protein function. ClinVar contains an entry for this variant (Variation ID: 553809). (less)
Likely pathogenic (Dec 11, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV003932980.2 First in ClinVar: Jun 24, 2023 Last updated: Jul 23, 2024	Comment: Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein … (more) Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 36100708, 26809805) (less)
Likely pathogenic (Aug 29, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal dominant Alport syndrome Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV005368385.1 First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024	Comment: Criteria applied: PS4_MOD, PM5, PM1_SUP, PM2_SUP, PP3 Clinical Features: Proteinuria (present) , Glomerulopathy (present) Sex: female
Uncertain significance (Apr 21, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hematuria, benign familial, 1 (Autosomal unknown) Affected status: yes Allele origin: germline	Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center Accession: SCV005397380.1 First in ClinVar: Nov 17, 2024 Last updated: Nov 17, 2024	Publications: PubMed (3) PubMed: 26809805‚ 36100708‚ 11375996 Comment: This sequence variant is a single nucleotide substitution (G>A) at coding position 5048 of the COL4A4 gene that results in a cysteine to tyrosine amino … (more) This sequence variant is a single nucleotide substitution (G>A) at coding position 5048 of the COL4A4 gene that results in a cysteine to tyrosine amino acid change at residue 1683 of the COL4A4 protein. This variant falls within the Collagen IV NC1 domain which is important for association with other collagen proteins (PMID: 11375996). This is a previously reported variant (ClinVar) that has been observed in the literature in multiple individuals with COL4A4-related disorders (PMID: 36100708, 26809805). Bioinformatic tools predict that this variant would be damaging and the Tyr1683 residue is highly conserved across the vertebrate species examined. Functiol studies testing the effect of this variant on protein structure or activity have not been performed, to our knowledge. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider this to be a variant of uncertain significance. ACMG Criteria: PM2, PP3 (less)

Comment:

This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1683 of the COL4A4 protein (p.Cys1683Tyr). This missense change has been observed in individuals with clinical features of autosomal dominant Alport syndrome (PMID: 26809805; Invitae). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COL4A4 protein function. ClinVar contains an entry for this variant (Variation ID: 553809).

Comment:

Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 36100708, 26809805)

Comment:

This sequence variant is a single nucleotide substitution (G>A) at coding position 5048 of the COL4A4 gene that results in a cysteine to tyrosine amino acid change at residue 1683 of the COL4A4 protein. This variant falls within the Collagen IV NC1 domain which is important for association with other collagen proteins (PMID: 11375996). This is a previously reported variant (ClinVar) that has been observed in the literature in multiple individuals with COL4A4-related disorders (PMID: 36100708, 26809805). Bioinformatic tools predict that this variant would be damaging and the Tyr1683 residue is highly conserved across the vertebrate species examined. Functiol studies testing the effect of this variant on protein structure or activity have not been performed, to our knowledge. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider this to be a variant of uncertain significance. ACMG Criteria: PM2, PP3

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
Prevalence of hereditary tubulointerstitial kidney diseases in the German Chronic Kidney Disease study.	Popp B	European journal of human genetics : EJHG	2022	PMID: 36100708
Identification of 47 novel mutations in patients with Alport syndrome and thin basement membrane nephropathy.	Weber S	Pediatric nephrology (Berlin, Germany)	2016	PMID: 26809805
The NC1 domain of collagen IV encodes a novel network composed of the alpha 1, alpha 2, alpha 5, and alpha 6 chains in smooth muscle basement membranes.	Borza DB	The Journal of biological chemistry	2001	PMID: 11375996

Text-mined citations for rs1386495377 ...

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 19, 2024

ClinVar Genomic variation as it relates to human health

NM_000092.5(COL4A4):c.5048G>A (p.Cys1683Tyr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1386495377 ...