Submissions for variant NM_001845.6(COL4A1):c.3634A>T (p.Met1212Leu)

gnomAD frequency: 0.00017  dbSNP: rs199557190

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000315987	SCV000382382	likely benign	Porencephalic cyst	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000379128	SCV000382383	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV002248553	SCV000382384	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Athena Diagnostics	RCV000991611	SCV001143216	likely benign	not provided	2018-11-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000991611	SCV002336649	likely benign	not provided	2025-01-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000991611	SCV002759016	uncertain significance	not provided	2022-10-12	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003401312	SCV004122059	uncertain significance	not specified	2023-10-24	criteria provided, single submitter	clinical testing	Variant summary: COL4A1 c.3634A>T (p.Met1212Leu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 249008 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in COL4A1 causing Porencephaly 1, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.3634A>T in individuals affected with Porencephaly 1 and no experimental evidence demonstrating its impact on protein function have been reported. Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014; five submitters classified the variant as likely benign/benign and one submitter classified it as a variant of uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Revvity Omics, Revvity	RCV000991611	SCV004235408	uncertain significance	not provided	2023-03-02	criteria provided, single submitter	clinical testing