Submissions for variant NM_001845.6(COL4A1):c.2705C>T (p.Pro902Leu)

dbSNP: rs146134172

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001870978	SCV002135794	uncertain significance	not provided	2023-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 902 of the COL4A1 protein (p.Pro902Leu). This variant is present in population databases (no rsID available, gnomAD 0.002%). 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: 1370351). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Fulgent Genetics, Fulgent Genetics	RCV002478183	SCV002801554	uncertain significance	Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome; Brain small vessel disease 1 with or without ocular anomalies; Hemorrhage, intracerebral, susceptibility to; Retinal arterial tortuosity; Microangiopathy and leukoencephalopathy, pontine, autosomal dominant	2022-04-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002551089	SCV003593912	uncertain significance	Inborn genetic diseases	2021-07-15	criteria provided, single submitter	clinical testing	The c.2705C>T (p.P902L) alteration is located in exon 33 (coding exon 33) of the COL4A1 gene. This alteration results from a C to T substitution at nucleotide position 2705, causing the proline (P) at amino acid position 902 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987923	SCV004804133	uncertain significance	not specified	2024-01-04	criteria provided, single submitter	clinical testing	Variant summary: COL4A1 c.2705C>T (p.Pro902Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251384 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2705C>T has been reported in the literature as a VUS in an individual with microcephaly (Ganapathy_2019) and in an individual affected by recurrent intracerebral hemorrhages, with an onset at 71 years of age (Liu_2022). These reports do 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 publications have been ascertained in the context of this evaluation (PMID: 31069529, 35711275). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001870978	SCV005331588	uncertain significance	not provided	2023-06-09	criteria provided, single submitter	clinical testing	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; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31069529, 35711275)