11-77172782-G-GCAGCCA

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 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
• Publications: 0 publications found

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]

MYO7A Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P
• Usher syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, PanelApp Australia
• Usher syndrome type 1B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• autosomal dominant nonsyndromic hearing loss 11

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Usher syndrome type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 14 uncertain in NM_000260.4
• 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 VariationId is 43159.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000260.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO7A	NM_000260.4	MANE Select	c.1833_1838dupCAGCCA	p.Ser612_Gln613insHisSer	disruptive_inframe_insertion	Exon 16 of 49	NP_000251.3
	MYO7A	NM_001127180.2		c.1833_1838dupCAGCCA	p.Ser612_Gln613insHisSer	disruptive_inframe_insertion	Exon 16 of 49	NP_001120652.1
	MYO7A	NM_001369365.1		c.1800_1805dupCAGCCA	p.Ser601_Gln602insHisSer	disruptive_inframe_insertion	Exon 17 of 50	NP_001356294.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO7A	ENST00000409709.9	TSL:1 MANE Select	c.1833_1838dupCAGCCA	p.Ser612_Gln613insHisSer	disruptive_inframe_insertion	Exon 16 of 49	ENSP00000386331.3
	MYO7A	ENST00000458637.6	TSL:1	c.1833_1838dupCAGCCA	p.Ser612_Gln613insHisSer	disruptive_inframe_insertion	Exon 16 of 49	ENSP00000392185.2
	MYO7A	ENST00000409619.6	TSL:1	c.1800_1805dupCAGCCA	p.Ser601_Gln602insHisSer	disruptive_inframe_insertion	Exon 17 of 50	ENSP00000386635.2

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 v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.6
Mutation Taster		=23/77	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs397516290; hg19: chr11-76883828;