ClinVar Miner

Submissions for variant NM_207361.6(FREM2):c.4561A>C (p.Thr1521Pro)

gnomAD frequency: 0.00002  dbSNP: rs777697719
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV001109792 SCV001267163 uncertain significance Fraser syndrome 2 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, 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.
Fulgent Genetics, Fulgent Genetics RCV002491350 SCV002783175 uncertain significance Isolated cryptophthalmia; Fraser syndrome 2 2021-12-28 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002556150 SCV003285130 uncertain significance not provided 2022-02-10 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 1521 of the FREM2 protein (p.Thr1521Pro). This variant is present in population databases (rs777697719, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with FREM2-related conditions. ClinVar contains an entry for this variant (Variation ID: 881063). 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: "Deleterious"; 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 RCV002556149 SCV003696157 uncertain significance Inborn genetic diseases 2022-04-25 criteria provided, single submitter clinical testing The c.4561A>C (p.T1521P) alteration is located in exon 1 (coding exon 1) of the FREM2 gene. This alteration results from a A to C substitution at nucleotide position 4561, causing the threonine (T) at amino acid position 1521 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Breakthrough Genomics, Breakthrough Genomics RCV002556150 SCV005192131 uncertain significance not provided criteria provided, single submitter not provided

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