Submissions for variant NM_000092.5(COL4A4):c.2242G>A (p.Gly748Ser)

gnomAD frequency: 0.00002  dbSNP: rs762139460

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Fulgent Genetics, Fulgent Genetics	RCV000673217	SCV000893588	likely pathogenic	Autosomal recessive Alport syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001333199	SCV001525715	uncertain significance	Benign familial hematuria	2018-09-21	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. The c.2242G>A (p.G748S) variant was previously reported as heterozygous (without second allele) in five individuals from two unrelated families with familial microhematuria with or without focal segmental glomerulosclerosis [PMID 28632965]
Myriad Genetics, Inc.	RCV000673217	SCV002060392	uncertain significance	Autosomal recessive Alport syndrome	2021-11-03	criteria provided, single submitter	clinical testing	NM_000092.4(COL4A4):c.2242G>A(G748S) is a missense variant classified as a variant of uncertain significance in the context of COL4A4-related Alport syndrome. G748S has not been observed in cases with relevant disease. Functional assessments of this variant are not available in the literature. G748S has been observed in population frequency databases (gnomAD: ASJ 0.01%). In summary, there is insufficient evidence to classify NM_000092.4(COL4A4):c.2242G>A(G748S) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Invitae	RCV001855593	SCV002230436	pathogenic	not provided	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 748 of the COL4A4 protein (p.Gly748Ser). This variant is present in population databases (rs762139460, gnomAD 0.01%). This missense change has been observed in individuals with COL4A4-related conditions (PMID: 28632965). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 557121). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt COL4A4 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001855593	SCV002762423	uncertain significance	not provided	2022-06-10	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Affects a glycine residue in a Gly-X-Y motif in the triple helical region of the COL4A4 gene; This variant is associated with the following publications: (PMID: 31589614, 28632965, 33391746)
CeGaT Center for Human Genetics Tuebingen	RCV001855593	SCV003916251	likely pathogenic	not provided	2023-08-01	criteria provided, single submitter	clinical testing	COL4A4: PM1:Strong, PM2, PP1, PP3, PP4