X-53403618-G-A
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong
The NM_006306.4(SMC1A):c.2368C>T(p.Arg790Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R790Q) has been classified as Pathogenic.
Frequency
Consequence
NM_006306.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMC1A | NM_006306.4 | c.2368C>T | p.Arg790Trp | missense_variant | 15/25 | ENST00000322213.9 | |
SMC1A | NM_001281463.1 | c.2302C>T | p.Arg768Trp | missense_variant | 16/26 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMC1A | ENST00000322213.9 | c.2368C>T | p.Arg790Trp | missense_variant | 15/25 | 1 | NM_006306.4 | P1 | |
SMC1A | ENST00000375340.10 | c.2302C>T | p.Arg768Trp | missense_variant | 16/26 | 1 | |||
SMC1A | ENST00000675504.1 | c.2302C>T | p.Arg768Trp | missense_variant | 15/25 | ||||
SMC1A | ENST00000674590.1 | c.1600C>T | p.Arg534Trp | missense_variant | 13/23 |
Frequencies
GnomAD3 genomes Cov.: 22
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 22
ClinVar
Submissions by phenotype
Congenital muscular hypertrophy-cerebral syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 27, 2019 | For these reasons, this variant has been classified as Pathogenic. A different missense substitution at this codon (p.Arg790Gln) has been determined to be pathogenic (PMID: 17273969, 25125236). This suggests that the arginine residue is critical for SMC1A protein function and that other missense substitutions at this position may also be pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been reported to be de novo in an individual affected with Cornelia de Lange syndrome (PMID: 25125236). ClinVar contains an entry for this variant (Variation ID: 159950). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with tryptophan at codon 790 of the SMC1A protein (p.Arg790Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | May 01, 2014 | - - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 21, 2017 | The p.R790W variant (also known as c.2368C>T), located in coding exon 15 of the SMC1A gene, results from a C to T substitution at nucleotide position 2368. The arginine at codon 790 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration was detected as a de novo occurrence in an individual with either a possible or confirmed diagnosis of Cornelia de Lange Syndrome (CdLS) (Ansari M et al. J. Med. Genet., 2014 Oct;51:659-68; Moss J et al. Am. J. Med. Genet. A, 2017 Jun;173:1566-1574). A different alteration located at the same position, p.R790Q (c.2369G>A), has been detected as de novo occurrences in three individuals: one with a CdLS phenotype of moderate severity, and two with possible or confirmed diagnoses of CdLS (Ansari M et al. J. Med. Genet., 2014 Oct;51:659-68; Gervasini C et al. Am. J. Med. Genet. A, 2013 Nov;161A:2909-19; Deardorff MA et al. Am. J. Hum. Genet., 2007 Mar;80:485-94). This amino acid position is highly conserved in available vertebrate species. In addition, the p.R790W alteration is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Microcephaly Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | Department of Pediatrics, Samsung Medical Center, Samsung Medical Center | - | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 14, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17273969, 24124034, 28425213, 25125236, 33584783, 16604071) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at