rs775373641

Variant names:

• chr2-227247559-G-T
• rs775373641
• NM_000091.5:c.443G>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM5 PP3 PP5_Very_Strong

The NM_000091.5(COL4A3):​c.443G>T​(p.Gly148Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000198 in 1,613,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G148D) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: COL4A3 NM_000091.5 missense, splice_region
• Scores: Splicing: ADA: 0.9788
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 U:2
• Conservation: PhyloP100: 4.91
• Publications: 6 publications found

Genes affected

COL4A3 (HGNC:2204): (collagen type IV alpha 3 chain) Type IV collagen, the major structural component of basement membranes, is a multimeric protein composed of 3 alpha subunits. These subunits are encoded by 6 different genes, alpha 1 through alpha 6, each of which can form a triple helix structure with 2 other subunits to form type IV collagen. This gene encodes alpha 3. In the Goodpasture syndrome, autoantibodies bind to the collagen molecules in the basement membranes of alveoli and glomeruli. The epitopes that elicit these autoantibodies are localized largely to the non-collagenous C-terminal domain of the protein. A specific kinase phosphorylates amino acids in this same C-terminal region and the expression of this kinase is upregulated during pathogenesis. This gene is also linked to an autosomal recessive form of Alport syndrome. The mutations contributing to this syndrome are also located within the exons that encode this C-terminal region. Like the other members of the type IV collagen gene family, this gene is organized in a head-to-head conformation with another type IV collagen gene so that each gene pair shares a common promoter. [provided by RefSeq, Jun 2010]

MFF-DT (HGNC:41067): (MFF divergent transcript)

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-227247559-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3336422.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 2-227247559-G-T is Pathogenic according to our data. Variant chr2-227247559-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 551046.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A3	NM_000091.5	c.443G>T	p.Gly148Val	missense_variant, splice_region_variant	Exon 8 of 52	ENST00000396578.8	NP_000082.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A3	ENST00000396578.8	c.443G>T	p.Gly148Val	missense_variant, splice_region_variant	Exon 8 of 52	1	NM_000091.5	ENSP00000379823.3

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152074 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 249524 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461812 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 727214

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000234 AC: 26 AN: 1111948

Other (OTH) AF: 0.0000497 AC: 3 AN: 60392

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152074 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74268

African (AFR) AF: 0.00 AC: 0 AN: 41394

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000248 AC: 3

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Oct 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 148 of the COL4A3 protein (p.Gly148Val). This variant is present in population databases (rs775373641, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of focal segmental glomerulosclerosis, steroid resistant nephrotic syndrome, or Alport syndrome (PMID: 25229338, 30406062; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 551046). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic.

Apr 09, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The COL4A3 c.443G>T; p.Gly148Val variant (rs775373641) is reported in the literature in individuals diagnosed with Alport syndrome, glomerulosclerosis, steroid resistant nephrotic syndrome, or hearing loss (Boeckhaus 2021, Boucher 2020, Malone 2014, Varner 2018). The variant is listed in the ClinVar database (Variation ID: 551046) and is listed in the general population with an overall allele frequency of 0.001% (4/280,874 alleles) in the Genome Aggregation Database. The glycine at codon 148 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.991). Additionally, this glycine occurs in a Gly-X-Y repeat region in a collagen triple helix region, a critical functional domain (Savige 2021). Based on available information, this variant is considered to be likely pathogenic. References: Boeckhaus J et al. Precise variant interpretation, phenotype ascertainment, and genotype-phenotype correlation of children in the EARLY PRO-TECT Alport trial. Clin Genet. 2021 Jan;99(1):143-156. PMID: 33040356. Boucher S et al. Ultrarare heterozygous pathogenic variants of genes causing dominant forms of early-onset deafness underlie severe presbycusis. Proc Natl Acad Sci U S A. 2020 Dec 8;117(49):31278-31289. PMID: 33229591. Malone AF et al. Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis. Kidney Int. 2014 Dec;86(6):1253-9. PMID: 25229338. Savige J et al. Consensus statement on standards and guidelines for the molecular diagnostics of Alport syndrome: refining the ACMG criteria. Eur J Hum Genet. 2021 Aug;29(8):1186-1197. PMID: 33854215. Varner JD et al. Genetic Testing for Steroid-Resistant-Nephrotic Syndrome in an Outbred Population. Front Pediatr. 2018 Oct 22;6:307. PMID: 30406062.

Mar 15, 2023

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. The majority of the pathogenic variants in this gene involve the substitution of a glycine residue in the triple-helix domain, resulting in disruption of protein function (PMID: 29632050, 21421911, 19344236). This variant alters a critical location within the protein, and is expected to severely affect function and cause disease.

Autosomal recessive Alport syndrome Pathogenic:1 Uncertain:1

Jan 04, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: COL4A3 c.443G>T (p.Gly148Val) results in a non-conservative amino acid change located in the triple-helical region (Uniprot) of the encoded protein sequence. Alterations of glycine residues within the collagen triple-helix are common mechanisms of disease. Five of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. The variant allele was found at a frequency of 1.2e-05 in 249524 control chromosomes (gnomAD). c.443G>T has been reported in the literature in the heterozygous state in individual(s) with clinical features of focal segmental glomerulosclerosis and steroid resistant nephrotic syndrome (Malone_2014, Varner_2018), and in a heterozygous individual with Alport Syndrome who had a positive family history of the disease (Boeckhaus_2021). It has also been reported in an individual affected with hearing loss, but with no other reported features of Alport Syndrome (Boucher_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments, classifying the variant as either VUS (n=2) or pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.

Mar 23, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Alport syndrome Pathogenic:1 Uncertain:1

Jul 30, 2025

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is present in gnomAD <0.01 (v4: 32 heterozygote(s), 0 homozygote(s)); This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in heterozygous individuals with familial focal segmental glomerulosclerosis, Alport syndrome and age-related hearing loss (PMID: 25229338, 33040356, 33229591). In addition, it has been classified as pathogenic and likely pathogenic by multiple clinical laboratories (ClinVar); Variant is located in the well-established functional Gly-X-Y motif in the collagen triple helical domain (DECIPHER); Missense variant predicted to be damaging by in silico tool(s) or highly conserved with a major amino acid change. Additional information: Variant is predicted to result in a missense amino acid change from glycine to valine; This variant is heterozygous; This gene is associated with both recessive and dominant Alport syndrome (MONDO:0018965), COL4A3-related; Alternative amino acid change(s) at the same position are present in gnomAD (highest allele count: v4: 1 heterozygote(s), 0 homozygote(s)) ; No published segregation evidence has been identified for this variant; No published functional evidence has been identified for this variant; Another missense variant comparable to the one identified in this case has conflicting previous evidence for pathogenicity. p.(Gly148Asp) has been classified as likely pathogenic and as a variant of uncertain significance by clinical laboratories (ClinVar); Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with Alport syndrome (MONDO:0018965), COL4A3-related. Glycine changes that are part of a G-X-Y repeat in the triple helix of a collagen domain are known to have a dominant negative effect (PMID: 12028435); Inheritance information for this variant is not currently available in this individual.

Sep 16, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

COL4A3-related disorder Pathogenic:1

Sep 06, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The COL4A3 c.443G>T variant is predicted to result in the amino acid substitution p.Gly148Val. This variant has been reported in the heterozygous state in individuals with focal segmental glomerulosclerosis (FSGS) or Alport syndrome related phenotypes (Malone et al. 2014. PubMed ID: 25229338; Varner et al. 2018. PubMed ID: 30406062; Supplementary Table 2, Ćomić et al. 2022. PubMed ID: 36117978; Boeckhaus et al. 2020. PubMed ID: 33040356). This variant was also reported in the heterozygous state in a patient with age-related hearing loss (PT 4011 in Boucher et al. 2020. PubMed ID: 33229591). The p.Gly148 residue is located in the conserved triple helical domain, where substitutions of the glycine are usually pathogenic (UniProt residues 43-1438, Hudson et al. 1993. PubMed ID: 8253711; https://www.ncbi.nlm.nih.gov/books/NBK21582/). In addition, at other glycine (Gly) residues within this domain, substitutions of a glycine (Gly) with a valine (Val) have been widely reported to be pathogenic for autosomal dominant or recessive COL4A3 nephropathy (see for example, p.Gly464Val in Tazon Vega et al. 2003. PubMed ID: 14582039, autosomal recessive and dominant in the same family; p.Gly631Val in Weber et al. 2016. PubMed ID: 26809805 and Braunisch et al. 2018. PubMed ID: 29946535, autosomal dominant; p.Gly795Val in Supplementary Table 3, Bullich et al. 2018. PubMed ID: 29801666, autosomal dominant). The c.443G>T (p.Gly148Val) variant is reported in 0.0097% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. In summary, this variant is interpreted as pathogenic for both autosomal dominant and recessive COL4A3 nephropathy.

Hematuria, benign familial, 2;C5882663:Autosomal dominant Alport syndrome;C5882699:Alport syndrome 3b, autosomal recessive Pathogenic:1

Feb 02, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal dominant Alport syndrome Pathogenic:1

Nov 27, 2018

Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		4.9
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-7.2	D
REVEL	Pathogenic	0.99
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Vest4		0.97
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.91
gMVP		0.98
Mutation Taster		=30/70	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.84
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs775373641; hg19: chr2-228112275;