Submissions for variant NM_005912.3(MC4R):c.947T>G (p.Ile316Ser)

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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	RCV000778539	SCV000914824	likely pathogenic	Obesity	2017-04-28	criteria provided, single submitter	clinical testing	The MC4R c.947T>G (p.Ile316Ser) variant has been reported in three studies in which it is found in a total of eight obese individuals from three families (Farooqi et al. 2003; Saeed et al. 2012; Saeed et al. 2015). The variant was identified in a homozygous state in three affected individuals, including a sibling pair, from a consanguineous family and in another unrelated individual. Another family, in which the variant segregated with disease, included one affected homozygote and three affected heterozygotes who were less obese than the homozygote. The p.Ile316Ser variant was absent from 80 controls but is reported at a frequency of 0.00036 in the South Asian population of the Exome Aggregation Consortium. Functional studies conducted in cell lines demonstrated that the p.Ile316Ser variant results in partial loss of function and a 14-fold decrease in binding affinity for MSH analog as compared to wild type protein. Furthermore, the p.Ile316Ser protein was less abundant in the plasma membrane and localized in the endoplasmic reticulum as a ubiquitinated protein (Farooqi et al. 2003; Yeo et al. 2003; Granell et al. 2010). Based on the collective evidence, the p.Ile316Ser variant is classified as likely pathogenic for obesity. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Fulgent Genetics, Fulgent Genetics	RCV000015407	SCV002788001	pathogenic	BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20	2021-11-17	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000015407	SCV003832334	likely pathogenic	BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20	2021-12-23	criteria provided, single submitter	clinical testing
OMIM	RCV000015407	SCV000035668	pathogenic	BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20	2003-03-20	no assertion criteria provided	literature only

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