VCV000557121.29 - ClinVar

NM_000092.5(COL4A4):c.2242G>A (p.Gly748Ser)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(3); Uncertain significance(3)

7 out of 8 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000092.5(COL4A4):c.2242G>A (p.Gly748Ser)

Variation ID: 557121 Accession: VCV000557121.29

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q36.3 2: 227059546 (GRCh38) [ NCBI UCSC ] 2: 227924262 (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	Feb 25, 2025	May 14, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000092.5:c.2242G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000083.3:p.Gly748Ser	missense
NC_000002.12:g.227059546C>T
NC_000002.11:g.227924262C>T
NG_011592.1:g.110014G>A
LRG_231:g.110014G>A
LRG_231t1:c.2242G>A	LRG_231p1:p.Gly748Ser

... more HGVS ... less HGVS

Protein change

G748S

Other names

Canonical SPDI

NC_000002.12:227059545: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) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00003

Trans-Omics for Precision Medicine (TOPMed) 0.00003

Exome Aggregation Consortium (ExAC) 0.00004

Links

ClinGen: CA2144855 dbSNP: rs762139460 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	3361	3399

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	Conflicting classifications of pathogenicity (2)	criteria provided, conflicting classifications	Nov 3, 2021	RCV000673217.9
Benign familial hematuria	Uncertain significance (1)	criteria provided, single submitter	Sep 21, 2018	RCV001333199.1
not provided	Conflicting classifications of pathogenicity (3)	criteria provided, conflicting classifications	Jan 31, 2024	RCV001855593.23
COL4A4-related disorder	Pathogenic (1)	no assertion criteria provided	Jun 10, 2024	RCV004737944.1
Autosomal recessive Alport syndrome Hematuria, benign familial, 1	Likely pathogenic (1)	criteria provided, single submitter	May 14, 2024	RCV005019154.1

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.
Likely pathogenic (Oct 31, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal recessive Alport syndrome Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893588.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Uncertain significance (Sep 21, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hematuria, benign familial, 1 Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV001525715.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Publications: PubMed (1) PubMed: 28632965 Comment: This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. The c.2242G>A (p.G748S) variant was previously reported as heterozygous (without … (more) This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. The c.2242G>A (p.G748S) variant was previously reported as heterozygous (without second allele) in five individuals from two unrelated families with familial microhematuria with or without focal segmental glomerulosclerosis [PMID 28632965] (less)
Uncertain significance (Nov 03, 2021) C Contributing to aggregate classification	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021)) Method: clinical testing	Autosomal recessive Alport syndrome Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV002060392.2 First in ClinVar: Jan 15, 2022 Last updated: Nov 29, 2022	Comment: NM_000092.4(COL4A4):c.2242G>A(G748S) is a missense variant classified as a variant of uncertain significance in the context of COL4A4-related Alport syndrome. G748S has not been observed in … (more) NM_000092.4(COL4A4):c.2242G>A(G748S) is a missense variant classified as a variant of uncertain significance in the context of COL4A4-related Alport syndrome. G748S has not been observed in cases with relevant disease. Functional assessments of this variant are not available in the literature. G748S has been observed in population frequency databases (gnomAD: ASJ 0.01%). In summary, there is insufficient evidence to classify NM_000092.4(COL4A4):c.2242G>A(G748S) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. (less)
Uncertain significance (Jun 10, 2022) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002762423.1 First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022	Comment: In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Affects a glycine residue in a Gly-X-Y motif in the … (more) In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Affects a glycine residue in a Gly-X-Y motif in the triple helical region of the COL4A4 gene; This variant is associated with the following publications: (PMID: 31589614, 28632965, 33391746) (less)
Likely pathogenic (Aug 01, 2023) C Contributing to aggregate classification	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: SCV003916251.14 First in ClinVar: Apr 23, 2023 Last updated: Dec 22, 2024	Comment: COL4A4: PM1:Strong, PM2, PP1, PP3, PP4 Number of individuals with the variant: 2
Pathogenic (Jan 31, 2024) C Contributing to aggregate classification	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: SCV002230436.4 First in ClinVar: Mar 28, 2022 Last updated: Feb 25, 2025	Publications: PubMed (1) PubMed: 28632965 Comment: This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 748 of the COL4A4 protein (p.Gly748Ser). … (more) This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 748 of the COL4A4 protein (p.Gly748Ser). This variant is present in population databases (rs762139460, gnomAD 0.01%). This missense change has been observed in individuals with COL4A4-related conditions (PMID: 28632965). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 557121). 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) performed at Invitae indicates that this missense variant is expected to disrupt COL4A4 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (May 14, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hematuria, benign familial, 1 Autosomal recessive Alport syndrome Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Fulgent Genetics, Fulgent Genetics Accession: SCV005649121.1 First in ClinVar: Jan 25, 2025 Last updated: Jan 25, 2025
Pathogenic (Jun 10, 2024) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	COL4A4-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005360865.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The COL4A4 c.2242G>A variant is predicted to result in the amino acid substitution p.Gly748Ser. The Gly748Ser variant affects a Gly residue of the conserved triple … (more) The COL4A4 c.2242G>A variant is predicted to result in the amino acid substitution p.Gly748Ser. The Gly748Ser variant affects a Gly residue of the conserved triple helical domain (residues 65 – 1459) of the COL4A4 protein (uniprot.org). The majority of pathogenic variants in COL4A4 substitute a glycine residue to a bulkier amino acid in the triple-helical domain (Hudson et al. 1993. PubMed ID: 8253711; https://www.ncbi.nlm.nih.gov/books/NBK1207/). This variant was reported in two individuals with focal segmental glomerulosclerosis and was shown to segregate with disease in one family (Papazachariou et al 2017. PubMed ID: 28632965). At PreventionGenetics, we have observed this variant in the heterozygous state in four individuals with COL4A4-related phenotypes and it segregated with disease in one family (Internal Data). This variant is reported in 0.0097% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as pathogenic. (less)

Comment:

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. The c.2242G>A (p.G748S) variant was previously reported as heterozygous (without second allele) in five individuals from two unrelated families with familial microhematuria with or without focal segmental glomerulosclerosis [PMID 28632965]

Comment:

NM_000092.4(COL4A4):c.2242G>A(G748S) is a missense variant classified as a variant of uncertain significance in the context of COL4A4-related Alport syndrome. G748S has not been observed in cases with relevant disease. Functional assessments of this variant are not available in the literature. G748S has been observed in population frequency databases (gnomAD: ASJ 0.01%). In summary, there is insufficient evidence to classify NM_000092.4(COL4A4):c.2242G>A(G748S) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.

Comment:

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Affects a glycine residue in a Gly-X-Y motif in the triple helical region of the COL4A4 gene; This variant is associated with the following publications: (PMID: 31589614, 28632965, 33391746)

Comment:

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 748 of the COL4A4 protein (p.Gly748Ser). This variant is present in population databases (rs762139460, gnomAD 0.01%). This missense change has been observed in individuals with COL4A4-related conditions (PMID: 28632965). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 557121). 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) performed at Invitae indicates that this missense variant is expected to disrupt COL4A4 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.

Comment:

The COL4A4 c.2242G>A variant is predicted to result in the amino acid substitution p.Gly748Ser. The Gly748Ser variant affects a Gly residue of the conserved triple helical domain (residues 65 – 1459) of the COL4A4 protein (uniprot.org). The majority of pathogenic variants in COL4A4 substitute a glycine residue to a bulkier amino acid in the triple-helical domain (Hudson et al. 1993. PubMed ID: 8253711; https://www.ncbi.nlm.nih.gov/books/NBK1207/). This variant was reported in two individuals with focal segmental glomerulosclerosis and was shown to segregate with disease in one family (Papazachariou et al 2017. PubMed ID: 28632965). At PreventionGenetics, we have observed this variant in the heterozygous state in four individuals with COL4A4-related phenotypes and it segregated with disease in one family (Internal Data). This variant is reported in 0.0097% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as pathogenic.

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
Frequent COL4 mutations in familial microhematuria accompanied by later-onset Alport nephropathy due to focal segmental glomerulosclerosis.	Papazachariou L	Clinical genetics	2017	PMID: 28632965

Text-mined citations for rs762139460 ...

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 Feb 26, 2025

ClinVar Genomic variation as it relates to human health

NM_000092.5(COL4A4):c.2242G>A (p.Gly748Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs762139460 ...