NM_006306.4:c.2368C>T

Variant names:

• chrX-53403618-G-A
• rs587784412
• NM_006306.4:c.2368C>T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_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 (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: SMC1A NM_006306.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 1.67

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 Pathogenic. Variant got 15 ACMG points.

• PM1: In a coiled_coil_region (size 275) in uniprot entity SMC1A_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_006306.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the SMC1A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 68 curated pathogenic missense variants (we use a threshold of 10). The gene has 31 curated benign missense variants. Gene score misZ: 6.4479 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.88
• PP5: Variant X-53403618-G-A is Pathogenic according to our data. Variant chrX-53403618-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 159950.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMC1A	NM_006306.4	c.2368C>T	p.Arg790Trp	missense_variant	Exon 15 of 25	ENST00000322213.9	NP_006297.2
SMC1A	NM_001281463.1	c.2302C>T	p.Arg768Trp	missense_variant	Exon 16 of 26		NP_001268392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMC1A	ENST00000322213.9	c.2368C>T	p.Arg790Trp	missense_variant	Exon 15 of 25	1	NM_006306.4	ENSP00000323421.3
SMC1A	ENST00000375340.10	c.2302C>T	p.Arg768Trp	missense_variant	Exon 16 of 26	1		ENSP00000364489.7
SMC1A	ENST00000675504.1	c.2302C>T	p.Arg768Trp	missense_variant	Exon 15 of 25			ENSP00000502524.1
SMC1A	ENST00000674590.1	c.1600C>T	p.Arg534Trp	missense_variant	Exon 13 of 23			ENSP00000502626.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital muscular hypertrophy-cerebral syndrome Pathogenic:3

Oct 09, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Cornelia de Lange syndrome 2 (MIM#300590) and developmental and epileptic encephalopathy 85, with or without midline brain defects (MIM#301044). Dominant negative is a suggested mechanism of disease for missense variants (PMID: 17273969, 19701948). (I). 0110 - This gene is associated with X-linked dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. p.(Arg790Gln) has been classified as pathogenic by clinical laboratories in ClinVar. (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic or likely pathogenic by clinical laboratories in ClinVar. It has also been observed as heterozygous or hemizygous in individuals with Cornelia de Lange syndrome in the literature, including at least 1 de novo occurence (PMID: 28425213, 33584783, 25125236). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) by trio analysis. (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

May 01, 2014

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 27, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant is not present in population databases (ExAC no frequency). 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). 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. 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. For these reasons, this variant has been classified as Pathogenic. -

Microcephaly Pathogenic:1

-

Department of Pediatrics, Samsung Medical Center, Samsung Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Inborn genetic diseases Pathogenic:1

Nov 21, 2017

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Pathogenic:1

Mar 25, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17273969, 24124034, 28425213, 25125236, 33584783, 16604071, 39831465, 38178268) -

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	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.69	D;D
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Pathogenic	3.1	M;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-7.1	D;.
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.81
MutPred		0.63		Loss of MoRF binding (P = 0.1412);.;
MVP		0.96
MPC		2.8
ClinPred		1.0	D
GERP RS		3.7
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.90
gMVP		0.89

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: rs587784412; hg19: chrX-53430550; COSMIC: COSV59129080; COSMIC: COSV59129080;