chrX-53412949-CCTT-C

Variant names:

• chrX-53412949-CCTT-C
• rs727503773
• NM_006306.4:c.802_804delAAG

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP3

The NM_006306.4(SMC1A):​c.802_804delAAG​(p.Lys268del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: SMC1A NM_006306.4 conservative_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.67

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-53412949-CCTT-C is Pathogenic according to our data. Variant chrX-53412949-CCTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 180197.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-53412949-CCTT-C is described in Lovd as [Pathogenic].
• BP3: Nonframeshift variant in repetitive region in NM_006306.4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMC1A	NM_006306.4	c.802_804delAAG	p.Lys268del	conservative_inframe_deletion	Exon 5 of 25	ENST00000322213.9	NP_006297.2
SMC1A	NM_001281463.1	c.736_738delAAG	p.Lys246del	conservative_inframe_deletion	Exon 6 of 26		NP_001268392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMC1A	ENST00000322213.9	c.802_804delAAG	p.Lys268del	conservative_inframe_deletion	Exon 5 of 25	1	NM_006306.4	ENSP00000323421.3

Frequencies

GnomAD3 genomes Cov.: 22

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital muscular hypertrophy-cerebral syndrome Pathogenic:5

May 13, 2021

Pediatric Genetics Clinic, Sheba Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 25, 2021

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 02, 2014

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jul 17, 2023

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) 0214 - In-frame deletion fully contained in a repetitive region that has high conservation. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - A missense variant at the same position has been observed in gnomAD (v2) (0 heterozygotes, 0 homozygotes, 1 hemizygote). (I) 0600 - Variant is located in the annotated RecF/RecN/SMC N terminal domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by several clinical laboratories in ClinVar and observed in many individuals with Cornelia de Lange syndrome in the literature (PMIDs: 28548707, 19701948, 25574841, 20358602). (SP) 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 -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SMC1A-related disorder Pathogenic:1

Jul 22, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SMC1A c.802_804delAAG variant is predicted to result in an in-frame deletion (p.Lys268del). This variant has been reported as a recurrent de novo variant in individuals with Cornelia de Lange syndrome (Liu et al. 2009. PubMed ID: 19701948; Yuan et al. 2019. PubMed ID: 30158690; Stojanovic et al. 2019. PubMed ID: 31623504; Table S1, Pode-Shakked et al. 2021. PubMed ID: 34580403; Kaur et al. 2023. PubMed ID: 37377026). This variant has not been reported in the gnomAD database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Hirsutism;C0026826:Hypertonia;C0241654:Abnormal heart valve morphology;C0557874:Global developmental delay;C1843156:Progressive sensorineural hearing impairment;C4551563:Microcephaly Pathogenic:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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: rs727503773; hg19: chrX-53439899;