Submissions for variant NM_000091.5(COL4A3):c.443G>T (p.Gly148Val)

gnomAD frequency: 0.00001  dbSNP: rs775373641

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000666006	SCV000790236	uncertain significance	Autosomal recessive Alport syndrome	2017-03-23	criteria provided, single submitter	clinical testing
Invitae	RCV001052837	SCV001217068	pathogenic	not provided	2024-01-28	criteria provided, single submitter	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; Invitae). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001052837	SCV003799822	likely pathogenic	not provided	2023-10-23	criteria provided, single submitter	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000666006	SCV003800625	likely pathogenic	Autosomal recessive Alport syndrome	2023-01-04	criteria provided, single submitter	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.
Athena Diagnostics	RCV001052837	SCV004229445	pathogenic	not provided	2023-03-15	criteria provided, single submitter	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.
PreventionGenetics, part of Exact Sciences	RCV003945699	SCV004759598	likely pathogenic	COL4A3-related disorder	2024-01-10	criteria provided, single submitter	clinical testing	The COL4A3 c.443G>T variant is predicted to result in the amino acid substitution p.Gly148Val. This variant was reported in 2 individuals with focal segmental glomerulosclerosis (Malone et al. 2014. PubMed ID: 25229338; Varner et al. 2018. PubMed ID: 30406062). This variant was also reported in a patient with age-related hearing loss (See 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/). This variant is reported in 0.0097% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as likely pathogenic for autosomal recessive COL4A3-disorders.
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000786994	SCV000925901	pathogenic	Autosomal dominant Alport syndrome	2018-11-27	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001272225	SCV001454002	uncertain significance	Alport syndrome	2020-09-16	no assertion criteria provided	clinical testing