18-6956661-A-AGCTTGCT

Position:

• chr18-6956661-A-AGCTTGCT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The ENST00000389658.4(LAMA1):​c.8068_8069insAGCAAGC​(p.Leu2690GlnfsTer42) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LAMA1 ENST00000389658.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.30

Genes affected

LAMA1 (HGNC:6481): (laminin subunit alpha 1) This gene encodes one of the alpha 1 subunits of laminin. The laminins are a family of extracellular matrix glycoproteins that have a heterotrimeric structure consisting of an alpha, beta and gamma chain. These proteins make up a major component of the basement membrane and have been implicated in a wide variety of biological processes including cell adhesion, differentiation, migration, signaling, neurite outgrowth and metastasis. Mutations in this gene may be associated with Poretti-Boltshauser syndrome. [provided by RefSeq, Sep 2014]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-6956661-A-AGCTTGCT is Pathogenic according to our data. Variant chr18-6956661-A-AGCTTGCT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 517432.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA1	NM_005559.4	c.8068_8069insAGCAAGC	p.Leu2690GlnfsTer42	frameshift_variant	56/63	ENST00000389658.4	NP_005550.2
LOC101927188	NR_126040.1	n.1539_1545dup		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMA1	ENST00000389658.4	c.8068_8069insAGCAAGC	p.Leu2690GlnfsTer42	frameshift_variant	56/63	1	NM_005559.4	ENSP00000374309	P1
	ENST00000584722.1	n.1539_1545dup		non_coding_transcript_exon_variant	2/2	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ataxia - intellectual disability - oculomotor apraxia - cerebellar cysts syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 29, 2017

The p.Leu2690GlnfsX42 (NM_005559.3 c.8062_8068dupAGCAAGC) variant in LAMA1 has not been previously reported in the literature and was absent from large populat ion studies. This variant is predicted to cause a frameshift, which alters the p rotein?s amino acid sequence beginning at position 2690 and leads to a premature termination codon 42 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Biallelic loss of function of the LAMA 1 gene has been associated with Poretti-Boltshauser syndrome. In summary, althou gh additional studies are required to fully establish a null effect on the prote in, the p.Leu2690GlnfsX42 variant in the LAMA1 gene is likely pathogenic for Por etti-Boltshauser syndrome in an autosomal recessive manner based on its predicte d impact on the protein. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555643185; hg19: chr18-6956660;