ClinVar Miner

Submissions for variant NM_000213.5(ITGB4):c.1345G>A (p.Gly449Ser)

gnomAD frequency: 0.00135  dbSNP: rs147963396
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV001122300 SCV001281013 uncertain significance Junctional epidermolysis bullosa with pyloric atresia 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.
Invitae RCV001355124 SCV002203702 likely benign not provided 2024-01-28 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002491379 SCV002781766 uncertain significance Junctional epidermolysis bullosa with pyloric atresia; Epidermolysis bullosa, junctional 5A, intermediate 2021-07-15 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001355124 SCV001549913 uncertain significance not provided no assertion criteria provided clinical testing The ITGB4 p.Gly449Ser variant was not identified in the literature nor was it identified in ClinVar, Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs147963396) and in control databases in 187 of 282486 chromosomes at a frequency of 0.000662 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 164 of 128888 chromosomes (freq: 0.001272), Other in 4 of 7218 chromosomes (freq: 0.000554), Latino in 11 of 35422 chromosomes (freq: 0.000311), European (Finnish) in 7 of 25110 chromosomes (freq: 0.000279) and South Asian in 1 of 30616 chromosomes (freq: 0.000033); it was not observed in the African, Ashkenazi Jewish or East Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Gly449 residue is not conserved in mammals or distantly related organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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