ClinVar Miner

Submissions for variant NM_020975.6(RET):c.1891G>A (p.Asp631Asn) (rs377767406)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000564566 SCV000674829 uncertain significance Hereditary cancer-predisposing syndrome 2016-11-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Fulgent Genetics,Fulgent Genetics RCV000764898 SCV000896058 uncertain significance Congenital central hypoventilation; Hirschsprung disease 1; Multiple endocrine neoplasia, type 2b; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia, type 2a 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000519407 SCV000618423 uncertain significance not provided 2017-07-31 criteria provided, single submitter clinical testing The D631N variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported as a somatic variant in medullary thyroid cancer (Agrawal et al., 2013). Functional studies show D631N results in absent transforming activity and no independent dimerization, as compared to a known pathogenic variant. This suggests that D631N is not pathogenic (Asai et al., 1999). This variant was observed at an allele frequency of 0.05% (4/8626) in individuals of East Asian ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek et al., 2016). Since Aspartic Acid and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. This substitution occurs at a position that is not conserved and is located in the intracellular domain and Cystein-rich domain (Garcia-Barcelo et al., 2004). Based on currently available evidence, we consider D631N to be a variant of uncertain significance.
Invitae RCV000696792 SCV000825371 uncertain significance Multiple endocrine neoplasia, type 2 2019-01-02 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 631 of the RET protein (p.Asp631Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs377767406, ExAC 0.05%). This variant has not been reported in the literature in individuals with RET-related disease. ClinVar contains an entry for this variant (Variation ID: 24913). Experimental studies have shown that this missense change does not result in RET protein activation (PMID: 10049754). A different variant affecting this nucleotide (p.Asp631Tyr) has been determined to be pathogenic (PMID: 16839264, 10049754, 22274720). This suggests that this nucleotide is important for normal protein function, and that other variants at this position may also be pathogenic. 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.

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