ClinVar Miner

Submissions for variant NM_020975.6(RET):c.1901G>C (p.Cys634Ser) (rs75996173)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Human Genetics, University of Leipzig Medical Center RCV001262460 SCV001440349 pathogenic Multiple endocrine neoplasia, type 2b 2019-01-01 criteria provided, single submitter clinical testing
Invitae RCV000021824 SCV001590179 pathogenic Multiple endocrine neoplasia, type 2 2020-02-20 criteria provided, single submitter clinical testing This sequence change replaces cysteine with serine at codon 634 of the RET protein (p.Cys634Ser). The cysteine residue is highly conserved and there is a moderate physicochemical difference between cysteine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with multiple endocrine neoplasia type 2 (PMID: 8099202, 15592804, 28099363). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Cys380Ser in the literature. ClinVar contains an entry for this variant (Variation ID: 13910, 549793). 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: Possibly Damaging; Align-GVGD: Class C0). A different variant (c.1900T>A) giving rise to the same protein effect observed here (p.Cys634Ser) has been determined to be pathogenic (PMID: 15277225, 25143909, 21765987). This suggests that this variant is also likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000014926 SCV000035182 pathogenic Multiple endocrine neoplasia, type 2a 2002-05-09 no assertion criteria provided literature only
OMIM RCV000014927 SCV000035183 pathogenic Pheochromocytoma 2002-05-09 no assertion criteria provided literature only
Research and Development, ARUP Laboratories RCV000021824 SCV000042490 pathogenic Multiple endocrine neoplasia, type 2 2018-05-04 no assertion criteria provided literature only MEN2A or FMTC families. Youngest with MTC: 9 yr (PMID 25143909). Youngest with Pheo: 19 yr (PMID 28099363). In the oldest reference, codon 634 was called codon 380. Additional references: PMID 15277225, 8640806, 18062802 and 7874109. Has been found with another RET change, see c.[1901G>C;1921G>T].

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