Submissions for variant NM_001845.6(COL4A1):c.1858G>C (p.Ala620Pro)

gnomAD frequency: 0.00006  dbSNP: rs372803920

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV002248578	SCV000382466	likely benign	Brain small vessel disease 1 with or without ocular anomalies	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV000291100	SCV000382467	likely benign	Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV000345989	SCV000382468	uncertain significance	Porencephalic cyst	2016-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV001840485	SCV002099624	uncertain significance	not provided	2024-09-17	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis indicates that this missense variant does not alter protein structure/function; Occurs in the triple helical domain at the Y position in the canonical Gly-X-Y repeat; although this variant may have an effect on normal protein folding and function, missense substitution at the Y position is not a common mechanism of disease
Labcorp Genetics (formerly Invitae), Labcorp	RCV001840485	SCV002151163	uncertain significance	not provided	2024-11-16	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 620 of the COL4A1 protein (p.Ala620Pro). This variant is present in population databases (rs372803920, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with COL4A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 311061). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt COL4A1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Revvity Omics, Revvity	RCV001840485	SCV004235409	uncertain significance	not provided	2023-04-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004800383	SCV005423549	uncertain significance	not specified	2024-10-02	criteria provided, single submitter	clinical testing	Variant summary: COL4A1 c.1858G>C (p.Ala620Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 250104 control chromosomes (gnomAD). c.1858G>C has been reported in the literature in an individual suspected of having idiopathic cutaneous vasculitis along with several other variants in other genes (example: Omoyinmi_2017). This report does not provide unequivocal conclusions about association of the variant with Porencephaly 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 28750028). ClinVar contains an entry for this variant (Variation ID: 311061). Based on the evidence outlined above, the variant was classified as uncertain significance.