Submissions for variant NM_001379081.2(FREM1):c.1640C>G (p.Ala547Gly)

gnomAD frequency: 0.00019  dbSNP: rs201056172

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000377307	SCV000479109	uncertain significance	Oculotrichoanal syndrome	2018-01-12	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Cavalleri Lab, Royal College of Surgeons in Ireland	RCV001171324	SCV001328271	uncertain significance	Chronic kidney disease	2020-05-28	criteria provided, single submitter	research	PP3, BS1
Labcorp Genetics (formerly Invitae), Labcorp	RCV002523769	SCV003297806	uncertain significance	not provided	2022-04-19	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 547 of the FREM1 protein (p.Ala547Gly). This variant is present in population databases (rs201056172, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with FREM1-related conditions. ClinVar contains an entry for this variant (Variation ID: 366157). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Ambry Genetics	RCV004022115	SCV004871995	uncertain significance	Inborn genetic diseases	2021-07-27	criteria provided, single submitter	clinical testing	The c.1640C>G (p.A547G) alteration is located in exon 10 (coding exon 8) of the FREM1 gene. This alteration results from a C to G substitution at nucleotide position 1640, causing the alanine (A) at amino acid position 547 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Sydney Genome Diagnostics, Children's Hospital Westmead	RCV001328303	SCV001449325	uncertain significance	Congenital anomaly of kidney and urinary tract	2018-02-09	no assertion criteria provided	clinical testing	This individual is heterozygous for the variant, c.1640C>G p.(Ala547Gly), in the FREM1 gene. To our knowledge, this variant has not been previously reported in the literature or any disease specific databases to be a disease causing variant. This variant has been reported in the gnomAD browser (http://gnomad.broadinstitute.org with a low allele frequency of 0.011% (33 out of 276,800 alleles). In silico analysis of pathogenicity (through Alamut Visual v2.8.1) is inconclusive regarding this change; PolyPhen2 and MutationTaster predicts it to be likely pathogenic whereas SIFT predicts this variant to be benign. This variant is considered to be a variant of uncertain clinical significance (VOUS) according to the ACMG guidelines.