VCV000637042.6 - ClinVar

NM_033380.3(COL4A5):c.4377del (p.Gly1460fs)

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.

Pathogenic/Likely pathogenic

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.4377del (p.Gly1460fs)

Variation ID: 637042 Accession: VCV000637042.6

Type and length

Deletion, 1 bp

Location

Cytogenetic: Xq22.3 X: 108687543 (GRCh38) [ NCBI UCSC ] X: 107930773 (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	Jul 27, 2019	Aug 25, 2024	Mar 1, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_033380.3:c.4377del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_203699.1:p.Gly1460fs	frameshift
NM_033380.3:c.4377delT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000495.4:c.4359del
NM_000495.5:c.4359del	NP_000486.1:p.Gly1454fs	frameshift
NC_000023.11:g.108687543del
NC_000023.10:g.107930773del
NG_011977.2:g.252620del
LRG_232:g.252620del
LRG_232t1:c.4359del	LRG_232p1:p.Gly1454fs
LRG_232t2:c.4377del	LRG_232p2:p.Gly1460fs

... more HGVS ... less HGVS

Protein change

G1460fs, G1454fs

Other names

Canonical SPDI

NC_000023.11:108687542: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.

Links

dbSNP: rs1603323174 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	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Feb 28, 2023	RCV000789032.5
not provided	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Mar 1, 2023	RCV003660835.3

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.
Pathogenic (May 24, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	X-linked Alport syndrome Affected status: yes Allele origin: de novo	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV000928369.1 First in ClinVar: Jul 27, 2019 Last updated: Jul 27, 2019	Comment: PVS1,PM1,PM2,PP2
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	X-linked Alport syndrome (X-linked dominant inheritance) Affected status: yes Allele origin: unknown	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India Accession: SCV003803639.1 First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023	Publications: pmc: 3872455 pmc: 3872455
Pathogenic (Feb 28, 2023)	criteria provided, single submitter (Li et al. (Genet Med. 2022)) Method: research	X-linked Alport syndrome Affected status: yes Allele origin: maternal	King Laboratory, University of Washington Accession: SCV003844195.1 First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023	Publications: PubMed (1) PubMed: 36633841 Comment: This variant was found in hemizygosity in a male patient with Alport syndrome, in a study of pediatric hearing loss conducted by the King Laboratory … (more) This variant was found in hemizygosity in a male patient with Alport syndrome, in a study of pediatric hearing loss conducted by the King Laboratory (Carlson RJ et al. JAMA-OtoHNS 2023). This patient has a maternal uncle with Alport syndrome, and his mother and grandmother also have renal abnormalities. The patient’s family has no other history of hearing loss. This variant is a single base pair deletion that causes a frameshift leading to the addition of 93 incorrect amino acids and an early stop at position 1547 of the 1691 amino acid COL4A5 protein. As of January 2023, this variant has been reported to ClinVar as pathogenic and is not found on gnomAD. Based on the prediction that this variant leads to a truncated protein, x-linked recessive inheritance pattern in the family, and goodness of fit of genotype to phenotype, we conclude that this variant is pathogenic. (less)
Pathogenic (Mar 01, 2023)	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: SCV004376170.1 First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024	Publications: PubMed (6) PubMed: 9195222‚ 10752524‚ 14514738‚ 24854265‚ 26809805‚ 34008892 Comment: For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 637042). This sequence change creates a … (more) For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 637042). This sequence change creates a premature translational stop signal (p.Gly1454Glufs*94) in the COL4A5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL4A5 are known to be pathogenic (PMID: 9195222, 10752524, 14514738, 24854265, 26809805). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with COL4A5-related conditions (PMID: 34008892). (less)
Likely pathogenic (Jul 13, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005197607.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024

Comment:

This variant was found in hemizygosity in a male patient with Alport syndrome, in a study of pediatric hearing loss conducted by the King Laboratory (Carlson RJ et al. JAMA-OtoHNS 2023). This patient has a maternal uncle with Alport syndrome, and his mother and grandmother also have renal abnormalities. The patient’s family has no other history of hearing loss. This variant is a single base pair deletion that causes a frameshift leading to the addition of 93 incorrect amino acids and an early stop at position 1547 of the 1691 amino acid COL4A5 protein. As of January 2023, this variant has been reported to ClinVar as pathogenic and is not found on gnomAD. Based on the prediction that this variant leads to a truncated protein, x-linked recessive inheritance pattern in the family, and goodness of fit of genotype to phenotype, we conclude that this variant is pathogenic.

Comment:

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 637042). This sequence change creates a premature translational stop signal (p.Gly1454Glufs*94) in the COL4A5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL4A5 are known to be pathogenic (PMID: 9195222, 10752524, 14514738, 24854265, 26809805). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with COL4A5-related conditions (PMID: 34008892).

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
Association of Genetic Diagnoses for Childhood-Onset Hearing Loss With Cochlear Implant Outcomes.	Carlson RJ	JAMA otolaryngology-- head & neck surgery	2023	PMID: 36633841
Phenotype-driven variant filtration strategy in exome sequencing toward a high diagnostic yield and identification of 85 novel variants in 400 patients with rare Mendelian disorders.	Marinakis NM	American journal of medical genetics. Part A	2021	PMID: 34008892
Identification of 47 novel mutations in patients with Alport syndrome and thin basement membrane nephropathy.	Weber S	Pediatric nephrology (Berlin, Germany)	2016	PMID: 26809805
Improving mutation screening in familial hematuric nephropathies through next generation sequencing.	Morinière V	Journal of the American Society of Nephrology : JASN	2014	PMID: 24854265
X-linked, COL4A5 hypomorphic Alport mutations such as G624D and P628L may only exhibit thin basement membrane nephropathy with microhematuria and late onset kidney failure.	Pierides A	Hippokratia	2013	PMC3872455
X-linked Alport syndrome: natural history and genotype-phenotype correlations in girls and women belonging to 195 families: a "European Community Alport Syndrome Concerted Action" study.	Jais JP	Journal of the American Society of Nephrology : JASN	2003	PMID: 14514738
X-linked Alport syndrome: natural history in 195 families and genotype- phenotype correlations in males.	Jais JP	Journal of the American Society of Nephrology : JASN	2000	PMID: 10752524
The clinical spectrum of type IV collagen mutations.	Lemmink HH	Human mutation	1997	PMID: 9195222

Text-mined citations for rs1603323174 ...

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.4377del (p.Gly1460fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1603323174 ...