ClinVar Genomic variation as it relates to human health

Variant summary: COL4A4 c.4715C>T (p.Pro1572Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 248514 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in COL4A4 causing Alport Syndrome, Autosomal Recessive (0.00016 vs 0.0016), allowing no conclusion about variant significance. c.4715C>T has been reported in the literature in individuals affected with Alport Syndrome, Autosomal Recessive. These reports do not provide unequivocal conclusions about association of the variant with Alport Syndrome, Autosomal Recessive. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign n=1, VUS n=4). Based on the evidence outlined above, the variant was classified as uncertain significance.

The c.4715C>T (p.P1572L) alteration is located in exon 47 (coding exon 46) of the COL4A4 gene. This alteration results from a C to T substitution at nucleotide position 4715, causing the proline (P) at amino acid position 1572 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Observed with a second variant in a patient with mesangial proliferative nephropathy in published literature (PMID: 25381091); 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: 31019026, 31589614, 32154576, 22887978, 35114279, 33772369, 36349777, 9792860, 34645491, 37097554, 36130833, 25381091, 39540369, 38972501)

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0103 - Loss of function is a known mechanism of disease for this gene and is associated with Alport syndrome. Dominant negative is a suspected mechanism of disease for this gene as it is a structural protein (PMID: 12028435, 24046192). (I) 0108 - This gene is associated with both recessive and dominant disease. Alport syndrome typically has biallelic inheritance, although rare cases of monoallelic inheritance have been reported (PMID: 28704582). Thin basement membrane nephropathy and focal segmental glomerulosclerosis are associated with autosomal dominant inheritance (OMIM, PMID: 16467446, 17942953). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2: 44 heterozygotes, 0 homozygotes, v3: 35 heterozygotes, 1 homozygote). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated collagen IV NC1 domain (PMID: 25381091, 9792860). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals.This variant has been classified as a VUS several times by diagnostic laboratories in ClinVar, and once as likely benign, but has also been classified as likely pathogenic or pathogenic many times in individuals with Alport syndrome. There is good evidence for the pathogenicity of this variant in autosomal recessive disease, and some evidence for pathogenicity in autosomal dominant disease (ClinVar, LOVD, PMID: 22887978, 25381091, 28976722, 31019026, 31246743, 31589614, 33772369, 9792860, 37097554). Recent literature also reports individuals who are heterozygous for this variant as unaffected carriers, or report other variants that account for their observed phenotype (PMID: 35114279, 36370330, 36349777, 37147621). (SP) 0906 - Segregation evidence for this variant is inconclusive. This variant has been observed in an unaffected parent (PMID: 25381091). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

The COL4A4 c.4715C>T variant is predicted to result in the amino acid substitution p.Pro1572Leu. This variant has been reported in the heterozygous state in individuals with suspected autosomal recessive Alport syndrome, although a second COL4A4 variant was not detected (Boye et al. 1998. PubMed ID: 9792860; Supplementary Table S1, De La Vega et al. 2021. PubMed ID: 34645491; Zhang et al. 2021. PubMed ID: 33772369). This variant has also been noted as paternally inherited in a compound heterozygote state in a patient with mesangial proliferative nephropathy (Lin et al. 2014. PubMed ID: 25381091) and in a heterozygous state in patients with IgA neuropathy and collagen III glomerulopathy (Liu et al. 2023. PubMed ID: 36370330; Table S5, Table S7, Yuan et al. 2022. PubMed ID: 36130833). This variant was also paternally inherited in an individual with anemia, nephritis, hepatitis, and recurrent gastroenteritis, but a second COL4A4 variant was not detected and phenotype information of the father was not available (Table S2, Table S15, Clark et al. 2019. PubMed ID: 31019026). Digenic inheritance and predisposition factors have been suggested for the combination of this variant with other genes because the variant has been noted in a patient with Alport syndrome who also carried a COL4A5 variant (Supplementary Table 1, Zhou et al. 2023. PubMed ID: 37097554), in a patient with concurrent IgA neuropathy and thin basement membrane nephropathy who also carried NPHS2 and ITGB4 variants (Xu et al. 2022. PubMed ID: 36349777), and a similar COL4A4 variant (p.Pro1569Leu) was noted in a patient who also carried a COL6A1 variant (Supplementary Table 1, Pan et al. 2020. PubMed ID: 32154576). The c.4715C>T variant is reported in 0.14% of alleles in individuals of East Asian descent in gnomAD, suggesting the variant may be too common for autosomal dominant disease. Although we suspect that the c.4715C>T variant may contribute to autosomal recessive COL4A4 disorders, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.