ClinVar Miner

Submissions for variant NM_020975.6(RET):c.1947G>A (p.Ser649=) (rs377767412)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000498649 SCV000589353 pathogenic not provided 2017-06-05 criteria provided, single submitter clinical testing The c.1947G>A variant in the RET gene was seen to segregate with disease in multiple families with Hirschsprung disease (Salomon et al., 1996; Bolk et al., 2000; Jiang et al., 2011). Although this variant is silent at the coding level, preserving a Serine at codon 649, it is predicted to cause abnormal splicing. Functional studies describe c.1947G>A as a hypomorphic allele, and state that carriers may express an intermediate level of RET (Bolk et al., 2000). This variant was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). The nucleotide which is altered, a guanine (G) at base 1947, is not conserved. Based on the currently available information, we consider c.1947G>A to be a pathogenic variant.
Fulgent Genetics,Fulgent Genetics RCV000762808 SCV000893159 likely pathogenic 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
Invitae RCV000821103 SCV000961846 likely pathogenic Multiple endocrine neoplasia, type 2 2018-09-29 criteria provided, single submitter clinical testing This sequence change affects codon 649 of the RET mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the RET protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with Hirschsprung disease in several families (PMID: 10618407, 21712996). ClinVar contains an entry for this variant (Variation ID: 24929). Experimental studies have shown that this silent change creates a novel splice acceptor site that is partially used in carriers (PMID: 10618407). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Research and Development, ARUP Laboratories RCV000021836 SCV000042502 uncertain significance not specified 2018-05-04 no assertion criteria provided literature only Three reports of HSCR. Possible splicing variant, and may require another locus (PMID 10090908 and 10618407). One individual report of FMTC index patient with p.S649S (genotype not published, PMID 16118333). Likely benign for MEN2 due to silent change.

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