ClinVar Miner

Submissions for variant NM_004992.3(MECP2):c.1214C>T (p.Pro405Leu) (rs61753016)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000132964 SCV000190998 uncertain significance not provided 2018-02-02 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MECP2 gene. The P405L variant has been reported previously as a de novo variant in the hemizygous state in an individual with cognitive impairment, ADHD, and stereotypic hand movements (Campos et al., 2009). The P405L variant has also been reported previously in the hemizygous state in an individual with cognitive impairment, epilepsy, autism, and stereotypic hand movements; whose mother and sister with borderline intelligence were found to be heterozyous for the variant (Moog et al., 2006). The P405L variant is observed in 8/27147 (0.03%) alleles from individuals of Latino background, including 2 unrelated hemizygous individuals in large population cohorts (Lek et al., 2016). The P405L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Integrated Genetics/Laboratory Corporation of America RCV000225647 SCV000282503 uncertain significance Rett syndrome 2015-07-29 criteria provided, single submitter clinical testing c.1214C>T (p.Pro405Leu) is a missense mutation that occurs at a conserved position, and 4/4 in silico tools predict a damaging outcome. Pro405 is a highly conserved amino acid in the carboxy terminal domain, which affects the binding of MECP2 to DNA. However, functional studies have not been carried out to determine the functional impact of this change. The variant has been observed in 1 hemizygous male control from the ExAC cohort, suggesting this variant could be low penetrance, benign, or a mild mutation. The variant has also been cited in at least 2 male intellectually disabled patients (1 de novo occurrence with no family history of ID and 1 maternally inherited with borderline intelligence on both sides of the family). Taken together, the c.1214C>T variant in MECP2 is classified as a variant of uncertain significance (VUS) until additional functional or co-segregation studies are available.
Invitae RCV000466180 SCV000556755 benign Angelman syndrome; Mental retardation, X-linked, syndromic 13; Rett syndrome 2016-07-22 criteria provided, single submitter clinical testing
RettBASE RCV000169944 SCV000187948 uncertain significance Mental retardation, X-linked, syndromic 13 2010-03-10 no assertion criteria provided curation

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