rs397516290

Variant names:

• chr11-77172782-G-GCAGCCA
• rs397516290
• NM_000260.4:c.1833_1838dupCAGCCA

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM4 PP5_Moderate

The NM_000260.4(MYO7A):​c.1833_1838dupCAGCCA​(p.Ser612_Gln613insHisSer) variant causes a disruptive inframe insertion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYO7A NM_000260.4 disruptive_inframe_insertion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.63

Genes affected

MYO7A (HGNC:7606): (myosin VIIA) This gene is a member of the myosin gene family. Myosins are mechanochemical proteins characterized by the presence of a motor domain, an actin-binding domain, a neck domain that interacts with other proteins, and a tail domain that serves as an anchor. This gene encodes an unconventional myosin with a very short tail. Defects in this gene are associated with the mouse shaker-1 phenotype and the human Usher syndrome 1B which are characterized by deafness, reduced vestibular function, and (in human) retinal degeneration. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000260.4.
• PP5: Variant 11-77172782-G-GCAGCCA is Pathogenic according to our data. Variant chr11-77172782-G-GCAGCCA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43159.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.1833_1838dupCAGCCA	p.Ser612_Gln613insHisSer	disruptive_inframe_insertion	Exon 16 of 49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.1833_1838dupCAGCCA	p.Ser612_Gln613insHisSer	disruptive_inframe_insertion	Exon 16 of 49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.1833_1838dupCAGCCA	p.Ser612_Gln613insHisSer	disruptive_inframe_insertion	Exon 16 of 49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.1800_1805dupCAGCCA	p.Ser601_Gln602insHisSer	disruptive_inframe_insertion	Exon 17 of 50	1		ENSP00000386635.2
MYO7A	ENST00000669443.1	c.195_200dupCAGCCA	p.Ser66_Gln67insHisSer	disruptive_inframe_insertion	Exon 3 of 3			ENSP00000499530.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rare genetic deafness Pathogenic:1

May 14, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Ser612_Gln613insHisSer variant (MYO7A) has not been reported in the literatu re nor previously reported by our laboratory. This variant results in an in-fram e insertion of two amino acids (Histidine and Serine) between position 612 and 6 13. Although more information is needed to fully assess the clinical significanc e of the Ser612_Gln613insHisSer variant, the addition of two amino acids is like ly to deleteriously impact protein function. This assumption, along with the ide ntification of this variant in a patient with Usher syndrome and another pathoge nic variant suggests this variant is likely pathogenic. -

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: rs397516290; hg19: chr11-76883828;