X-53413261-G-A

Variant names:

• chrX-53413261-G-A
• rs587784422
• NM_006306.4:c.586C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PM5 PP3_Moderate PP5

The NM_006306.4(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 NM_006306.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 5.48
• Publications: 4 publications found

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]

SMC1A Gene-Disease associations (from GenCC):

• Cornelia de Lange syndrome 2

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• developmental and epileptic encephalopathy, 85, with or without midline brain defects

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• atypical Rett syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cornelia de Lange syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 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 CliVar as Pathogenic. Clinvar id is 1076178.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159961. Variant chrX-53413261-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159961. Variant chrX-53413261-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159961. Variant chrX-53413261-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159961. Variant chrX-53413261-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159961. Variant chrX-53413261-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159961. Variant chrX-53413261-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159961. Variant chrX-53413261-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159961.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMC1A	ENST00000322213.9	c.586C>T	p.Arg196Cys	missense_variant	Exon 4 of 25	1	NM_006306.4	ENSP00000323421.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Sep 05, 2015

Baylor Genetics

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Dec 10, 2014

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 26, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 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). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with SMC1A-related conditions (PMID: 28924389). ClinVar contains an entry for this variant (Variation ID: 159961). 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. 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. -

Congenital muscular hypertrophy-cerebral syndrome;C5393312:Developmental and epileptic encephalopathy, 85, with or without midline brain defects Pathogenic:1

Feb 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;.;.
PhyloP100		5.5
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
Mutation Taster		=31/69	disease causing (ClinVar)

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

Other links and lift over

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