Submissions for variant NM_001039958.2(MESP2):c.401_411dup (p.Val138fs)

dbSNP: rs1218757887

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002223060	SCV002500687	uncertain significance	not specified	2022-03-28	criteria provided, single submitter	clinical testing	Variant summary: MESP2 c.401_411dup11 (p.Val138ThrfsX347) causes a frameshift which results in an extension of the protein. The variant was absent in 166732 control chromosomes (gnomAD). To our knowledge, no occurrence of c.401_411dup11 in individuals affected with Spondylocostal Dysostosis 2 and no experimental evidence demonstrating its impact on protein function have been reported. A similar protein extension, c.599delA (p.Gln200Argfs*281), has been reported in associated with abnormality of the skeletal system in HGMD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003669253	SCV004393703	pathogenic	not provided	2023-07-09	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with MESP2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the MESP2 gene (p.Val138Thrfs*347). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 260 amino acid(s) of the MESP2 protein and extend the protein by 86 additional amino acid residues. ClinVar contains an entry for this variant (Variation ID: 1677202). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the MESP2 protein in which other variant(s) (p.Gly169Profs*199) have been determined to be pathogenic (PMID: 15122512, 18485326). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown.