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

dbSNP: rs773081522

Total submissions: 8

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
Invitae	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