rs587784422

Positions:

• chrX-53413261-G-A
• chrX-53413261-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP2 PP3_Moderate PP5

The ENST00000322213.9(SMC1A):​c.586C>T​(p.Arg196Cys) variant causes a missense change. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R196G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: SMC1A ENST00000322213.9 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 5.48

Genes affected

SMC1A (HGNC:11111): (structural maintenance of chromosomes 1A) Proper cohesion of sister chromatids is a prerequisite for the correct segregation of chromosomes during cell division. The cohesin multiprotein complex is required for sister chromatid cohesion. This complex is composed partly of two structural maintenance of chromosomes (SMC) proteins, SMC3 and either SMC1B or the protein encoded by this gene. Most of the cohesin complexes dissociate from the chromosomes before mitosis, although those complexes at the kinetochore remain. Therefore, the encoded protein is thought to be an important part of functional kinetochores. In addition, this protein interacts with BRCA1 and is phosphorylated by ATM, indicating a potential role for this protein in DNA repair. This gene, which belongs to the SMC gene family, is located in an area of the X-chromosome that escapes X inactivation. Mutations in this gene result in Cornelia de Lange syndrome. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-53413261-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 1076178.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SMC1A. . Gene score misZ 6.4479 (greater than the threshold 3.09). GenCC has associacion of gene with Cornelia de Lange syndrome, X-linked complex neurodevelopmental disorder, atypical Rett syndrome, Cornelia de Lange syndrome 2, developmental and epileptic encephalopathy, 85, with or without midline brain defects.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.926
• PP5: Variant X-53413261-G-A is Pathogenic according to our data. Variant chrX-53413261-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 159961.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMC1A	NM_006306.4	c.586C>T	p.Arg196Cys	missense_variant	4/25	ENST00000322213.9	NP_006297.2
SMC1A	NM_001281463.1	c.520C>T	p.Arg174Cys	missense_variant	5/26		NP_001268392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMC1A	ENST00000322213.9	c.586C>T	p.Arg196Cys	missense_variant	4/25	1	NM_006306.4	ENSP00000323421	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital muscular hypertrophy-cerebral syndrome Pathogenic:2 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 26, 2022	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Arg196 amino acid residue in SMC1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17221863, 17273969). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SMC1A protein function. ClinVar contains an entry for this variant (Variation ID: 159961). This missense change has been observed in individual(s) with SMC1A-related conditions (PMID: 28924389). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 196 of the SMC1A protein (p.Arg196Cys). -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 10, 2014	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Baylor Genetics	Sep 05, 2015	Our laboratory reported dual molecular diagnoses in SMC1A (NM_006306.3, c.586C>T) and DMD (exon 49-51 deletion) in one individual with reported features of profound motor delay, bilateral hearing loss, diffused hypotonia, dysmorphia, cleft palate, microcephaly, vision loss, congenital heart disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.59	D;T;.
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Uncertain	2.6	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-7.6	D;.;.
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D;.;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.64
MutPred		0.75		Loss of MoRF binding (P = 0.0095);.;.;
MVP		0.91
MPC		3.3
ClinPred		1.0	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.91
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587784422; hg19: chrX-53440211; COSMIC: COSV59132231;