Submissions for variant NM_000529.2(MC2R):c.221G>T (p.Ser74Ile)

gnomAD frequency: 0.00033  dbSNP: rs104894658

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000003414	SCV000914807	pathogenic	Glucocorticoid deficiency 1	2018-12-19	criteria provided, single submitter	clinical testing	Across a selection of the available literature, the MCR2 c.221G>T (p.Ser74Ile) variant has been identified in upwards of 45 individuals with glucocorticoid deficiency in either a homozygous or compound heterozygous state (Clark and Weber 1994; Lin et al. 2007; Chan et al. 2009; Chung et al. 2010; Matthew et al. 2011; Tsai et al, 2016). The p.Ser74Ile variant is reported at a frequency of 0.00035 in the European American population of the Exome Sequencing Project. Functional assays performed by Fluck et al. (2002) and Elias et al. (1999) demonstrated that the p.Ser74Ile variant elicited virtually no measurable enzymatic activity and was associated with an impaired maximal cAMP response when compared to wild type. Based on the collective evidence, the p.Ser74Ile variant is classified as pathogenic for glucocorticoid deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000003414	SCV000996121	pathogenic	Glucocorticoid deficiency 1	2018-03-30	criteria provided, single submitter	clinical testing	This variant has been previously reported in multiple individuals affected with familial glucocorticoid deficiency (PMID: 8094489, 8069303, 26650942). Additionally, functional characterizations indicate that the p.Ser74Ile variant altered protein function relative to wild type protein (PMID: 12213892 10443676). The p.Ser74 residue is highly conserved, and in silico algorithms predict a damaging effect on protein function. The variant is rare, present as a heterozygous change in the population database gnomAD at a frequency of 0.01% (55/277226), but is not reported as a homozygous change. Based on the combined evidence, the variant is classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000003414	SCV002789695	pathogenic	Glucocorticoid deficiency 1	2022-04-26	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002512707	SCV003285382	pathogenic	not provided	2021-09-02	criteria provided, single submitter	clinical testing	This sequence change replaces serine with isoleucine at codon 74 of the MC2R protein (p.Ser74Ile). The serine residue is highly conserved and there is a large physicochemical difference between serine and isoleucine. This variant is present in population databases (rs104894658, ExAC 0.03%). This missense change has been observed in individuals with FGD and familial glucocorticoid deficiency (FGD) (PMID: 7829641, 12213892, 14960026, 17223989, 19170705, 26650942). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3258). 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: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects MC2R function (PMID: 8250922, 9758716, 18840636). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000003414	SCV003800803	pathogenic	Glucocorticoid deficiency 1	2023-01-07	criteria provided, single submitter	clinical testing	Variant summary: MC2R c.221G>T (p.Ser74Ile) results in a non-conservative amino acid change located in the GPCR, rhodopsin-like, 7TM domain (IPR017452) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 251482 control chromosomes. This frequency does not allow conclusions about variant significance. c.221G>T has been reported in the literature as biallelic homozygous or compound heterozygous genotypes in multiple individuals affected with Glucocorticoid Deficiency, due To ACTH unresponsiveness, a.k.a Familial Glucocorticoid Deficiency (FGD) (example, Weber_1994, Elias_1999, Buonocore_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, Elias_1999). The most pronounced variant effect results in an impaired maximal cAMP response due to low affinity for ACTH and no significant signal transducing ability. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000003414	SCV000023572	pathogenic	Glucocorticoid deficiency 1	1993-02-20	no assertion criteria provided	literature only
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000583288	SCV000692308	pathogenic	Glucocorticoid Deficiency	2009-01-23	no assertion criteria provided	clinical testing