ClinVar Miner

Submissions for variant NM_000092.5(COL4A4):c.1323_1340del (p.Pro444_Leu449del)

dbSNP: rs773081522
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000667405 SCV000791842 likely pathogenic Autosomal recessive Alport syndrome 2017-05-26 criteria provided, single submitter clinical testing
Molecular Biology Laboratory, Fundació Puigvert RCV000667405 SCV001425015 likely pathogenic Autosomal recessive Alport syndrome 2020-02-01 criteria provided, single submitter research
Labcorp Genetics (formerly Invitae), Labcorp RCV001386485 SCV001586722 pathogenic not provided 2023-10-05 criteria provided, single submitter clinical testing This variant, c.1323_1340del, results in the deletion of 6 amino acid(s) of the COL4A4 protein (p.Pro444_Leu449del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs773081522, gnomAD 0.03%). This variant has been observed in individual(s) with autosomal recessive and autosomal dominant Alport syndrome (PMID: 9792860, 25307543, 27281700, 30745910). 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. This variant is also known as 1527del18bp. ClinVar contains an entry for this variant (Variation ID: 552183). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic.
3billion RCV000667405 SCV002058985 pathogenic Autosomal recessive Alport syndrome 2022-01-03 criteria provided, single submitter clinical testing This inframe deletion in the non-repeat region can change the length of the protein and disrupt protein function (PM4_M). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 27281700, PMID: 30745910, PMID:9792860, PS4_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000552183, 3billion dataset). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000040, PM2_M). he variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 30745910, PM3_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Molecular Genetics, Royal Melbourne Hospital RCV002221245 SCV002498674 pathogenic Alport syndrome 2023-03-30 criteria provided, single submitter clinical testing This sequence change is predicted to cause a change in the length of the protein due to an in-frame deletion of six amino acids in a non-repeat region of the COL4A4 protein (p.(Pro444_Leu449del)). The region deleted is highly conserved (100 vertebrates, UCSC), and includes two glycines in Gly-X-Y repeats in the collagenous domain. The highest population minor allele frequency in gnomAD v2.1 is 0.03% (5/17,922 alleles, 0 homozygotes) in the East Asian population, which is consistent with a recessive condition. This variant has been reported in at least two probands autosomal dominant Alport syndrome (PMID: 25307543, 27281700). The variant has been reported to segregate with both dominant and recessive Alport syndrome in 11 affected family members from a single multi-generational family (PMID: 9792860). This variant has been detected in at least three individuals with Alport syndrome. Of those individuals, one individual was homozygous and two were compound heterozygous for the variant and a pathogenic variant confirmed in trans by parental testing (PMID: 9792860, 30745910, 33532864). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as PATHOGENIC. Following criteria are met: PM3_Strong, PP1_Strong, PM4, PM2_Supporting.
Fulgent Genetics, Fulgent Genetics RCV002493093 SCV002789414 pathogenic Autosomal recessive Alport syndrome; Benign familial hematuria 2021-12-21 criteria provided, single submitter clinical testing
Eurofins-Biomnis RCV003236586 SCV003935077 pathogenic Benign familial hematuria 2022-11-03 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV001386485 SCV004226742 pathogenic not provided 2023-06-23 criteria provided, single submitter clinical testing PP1, PM2_supporting, PM3, PM4, PS4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000667405 SCV005381024 pathogenic Autosomal recessive Alport syndrome 2024-08-15 criteria provided, single submitter clinical testing Variant summary: COL4A4 c.1323_1340del18 (p.Pro444_Leu449del) results in an in-frame deletion that is predicted to remove 6 amino acids within the triple-helical region (UniProt) of the encoded protein sequence. This variant disrupts critical glycine residues at position 1 of a Gly-X-Y repeat in the collagenous domain of the collagen IV alpha 4 chain, and variants affecting these glycine residues are significantly enriched in individuals with Alport syndrome (PMID: 33854215). The variant allele was found at a frequency of 4e-05 in 247640 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in COL4A4 causing Alport Syndrome, Autosomal Recessive (4e-05 vs 0.0011), allowing no conclusion about variant significance. c.1323_1340del18 has been reported in the literature in multiple individuals, including compound heterozygotes, homozygotes, and heterozygotes, affected with Alport Syndrome (e.g., Zhu_2018, Boye_1998, Domingo-Gallego_2022, Furlano_2021). These studies have shown segregation of the variant with disease among family members and suggest the variant is associated with both autosomal recessive and dominant forms of disease. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 38317457, 9792860, 33532864, 30745910). ClinVar contains an entry for this variant (Variation ID: 552183). Based on the evidence outlined above, the variant was classified as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV002221245 SCV005399568 pathogenic Alport syndrome 2023-07-17 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as 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 (PMIDs: 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 (TBMN) and focal segmental glomerulosclerosis (FSGS) are associated with autosomal dominant inheritance (OMIM, PMIDs: 16467446, 17942953). (I) 0216 - In-frame deletion in a non-repetitive region that has low conservation. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a condition (v2: 10 heterozygotes, 0 homozygotes). (SP) 0601 - Variant is located in the well-established functional Gly-X-Y motif in the collagen triple helical domain (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic and likely pathogenic by clinical laboratories in ClinVar and observed in multiple individuals with either autosomal dominant or autosomal recessive Alport syndrome (PMIDs: 27281700, 28704582, 30745910). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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