Submissions for variant NM_001927.4(DES):c.1255C>T (p.Pro419Ser)

dbSNP: rs62635763

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000056783	SCV000336776	likely pathogenic	not provided	2016-03-07	criteria provided, single submitter	clinical testing
Invitae	RCV000817811	SCV000958394	pathogenic	Desmin-related myofibrillar myopathy	2019-12-12	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change forms filaments and does not induce aggregation in cell lines (PMID: 23032110). This variant has been observed to segregate with autosomal dominant desminopathies in several families (PMID:17418574, 22153487, 22395865, 26431784). ClinVar contains an entry for this variant (Variation ID: 39718). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with serine at codon 419 of the DES protein (p.Pro419Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000817811	SCV004100543	pathogenic	Desmin-related myofibrillar myopathy		criteria provided, single submitter	clinical testing	The missense variant p.P419S in DES (NM_001927.4) has been previously reported in multiple patients with autosomal dominant desminopathies (Olivé M et al,Wahbi K et al). Functional studies reveal a damaging effect (Brodehl A et al). The variant has been submitted to ClinVar as Pathogenic.The p.P419S variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a moderate physicochemical difference between proline and serine. The p.P419S missense variant is predicted to be damaging by both SIFT and PolyPhen2. The proline residue at codon 419 of DES is conserved in all mammalian species. The nucleotide c.1255 in DES is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000817811	SCV000056695	pathogenic	Desmin-related myofibrillar myopathy	2012-09-01	no assertion criteria provided	literature only
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000056783	SCV000087896	not provided	not provided		no assertion provided	not provided
Department of Rehabilitation Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea	RCV000817811	SCV000882769	pathogenic	Desmin-related myofibrillar myopathy	2019-02-11	no assertion criteria provided	research